ANNUAL REPORT OF SCIENTIFIC ACTIVITY

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2011 ANNUAL REPORT OF SCIENTIFIC ACTIVITY

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2011

Neuropharmacology and neuroprotection. Neurotransmission in the hippocampus. Clinical pharmacology and pharmacogenetics. Diagnostic and therapeutic advances in affective disorders. Neurosurgery of epilepsy. Cerebrovascular diseases.

Prognostic and predictor markers in autoimmune diseases. Esophagogastrointestinal inflammatory diseases. Progenitors and cell therapy. Advanced therapies in oncohematology. Biological, cellular and molecular monitoring in oncohematology. New diagnostic and therapeutic advances in cardiovascular diseases. New therapies in infectious pathologies. Individualized medicine in solid tumors.

ANNUAL REPORT OF SCIENTIFIC ACTIVITY

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Intercellular Communication in the Inflammatory Response. Cellular and molecular responses to Hypoxia. Animal models of inflammatory diseases and intercellular signalling. Etiopathogenic and immunological mechanisms of dermatological diseases. Cellular mechanisms and molecular determinants of allergy-based diseases. Inflammatory processes in nephrological diseases. Inflammatory mechanisms in pulmonary diseases. Inflammatory response in hepatic diseases. Mechanisms and mediators of endocrine diseases. Children´s development (obesity and growth). Metabolic syndrome and vascular risk.

Letter from the Scientific Director

t is a great pleasure to present the 2011

I In 2011, despite the difficult economic environment, IIS-IP has maintained its commitment to consolidate research space and infrastructures and to support new emerging research groups

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Annual Scientific Report of the Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (La Princesa Hospital Institute for health Research. IISIP). Our Institute groups 449 researchers that conform 51 research teams distributed among the different centres that make up the IIS-IP (Hospital Universitario de La Princesa, Hospital Niño Jesús, Hospital Santa Cristina, Atención Primaria and Universidad Autónoma de Madrid). All our professionals work with strong dedication and commitment to improve the quality of our research aimed at the improvement of Public Health. This effort is reflected in the quality of our publications during 2011. In this year, IIS-IP researchers have published 249 articles in journals of first or second quartile with mean impact factor per article of 5.4. Of the total number of articles 51% were published in fist quartile journals and 23.7% in fist decile journals. In 2011, despite the difficult economic environment, IIS-IP has maintained its commitment to consolidate research space and infrastructures and to support new emerging research groups. We have allocated resources to fully equip 650 m2 of space for research in Santa Cristina Hospital creating a new

Research Unit. The new Unit has started this year with four brand new laboratories that host four emerging research groups. IIS-IP also obtained funding this year from Instituto de Salud Carlos III to tackle the refurbishment of the Central Research Unit in La Princesa Hospital. We make a constant effort to improve research infrastructures and facilities to ease the work of our professionals. The research activity of IIS-IP is organized in three main areas: 1. Cellular and molecular ethiopathogenic mechanisms in inflammatory and autoimmune diseases; 2. Neurotransmission pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases; and 3. Advanced therapies and individualized medicine. These research areas are integrated by 25 research lines that cover different aspects of basic, clinical and translational research. The scientific report presented here summarizes the configuration, research interests and activity during 2011 of all the different groups. We expect that it will show to the readers a clear perspective of our research and encourage everybody to keep working hard to improve in the future. Francisco Sánchez Madrid Scientific Director

INDEX Letter from the Scientific Director . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2011 ANNUAL REPORT OF SCIENTIFIC ACTIVITY

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

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Diego de León, 62 28006 Madrid Phone 91 520 24 76 Fax 91 520 25 60 e-mail: [email protected]

AREA 1 · CELLULAR AND MOLECULAR ETIOPATHOGENIC MECHANISMS IN INFLAMMATORY AND AUTOIMMUNE DISEASES . . . . . . . . . . . . . . . . .17 LINE 1.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19 LINE 1.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27 LINE 1.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42 LINE 1.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44 LINE 1.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46 LINE 1.7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50 LINE 1.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54 LINE 1.9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61 LINE 1.10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64 LINE 1.11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .68

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AREA 2 · NEUROTRANSMISSION, PHARMACOLOGICAL NEUROPROTECTION AND NEURODEGENERATIVE AND NEUROPSYCHIATRIC DISEASES . . . . . . .75 LINE 2.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77 LINE 2.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .83 LINE 2.3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .88 LINE 2.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92 LINE 2.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .97 LINE 2.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .100

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© INSTITUTO DE INVESTIGACIÓN SANITARIA Hospital Universitario de La Princesa

AREA 3 · ADVANCED THERAPIES AND INDIVIDUALIZED MEDICINE . . . . . . . . .107 LINE 3.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109 LINE 3.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119 LINE 3.3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .128 LINE 3.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .133 LINE 3.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .146 LINE 3.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .150 LINE 3.7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .158 LINE 3.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .171 –3–

SUMMARY

Summary Report Scientific Activity IIS-Princesa 2011

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SUMMARY SCIENTIFIC PRODUCTION The number of publications and their impact factor represents one of the best indicators of the quality of our research. In the last year 338 articles had been published in scientific journals included in the “Journal Citation Report (JCR)”.

factor. Each publication is ascribed to one group, although most of them are the result of the collaboration between different teams. The impact factor accumulated has reached 1483.775 with an average impact factor per article of 4.4.

The following graphic represents all these publications (distributed by areas) and their global impact

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Summary

CLINICAL TRIALS Clinical research is a fundamental pillar of development for our Institute. Coupled with the results of basic research, it seeks to improve the diagnosis and treatment of diseases, ultimately benefiting the patient. During 2011 a total of 436 clinical trials were carried out in our Institute. Their distribution by areas is shown below.

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Summary

DOCTORAL THESES As a result of the effort dedicated to training by our Institute fourteen PhD theses have been defended by

DOCTORATE THESIS READER

members of IIS-IP in 2011. Information about thee theses is summarized below.

TITLE

DIRECTOR

GROUP

Benedicto Español, Ignacio

Interrelación entre proteínas asociadas a uniones intercelulares estrechas, polaridad de los hepatocitos y el virus de la hepatitis C.

Pedro Lorenzo Majano Rodríguez

24

Blanco Sánchez, Ignacio

Estudio del efecto de darbepoetina α en isquemia7reperfusión renal. Su uso como agente protector y reparador del daño renal isquémico.

José Antonio Sánchez Tomero

21

Calderón Deago, Jossela

Implicación del receptor SLAM (CD150) en la infección por Trypanosoma cruzi

Manuel Fresno Escudero

12

Cardeñoso Domingo, Laura María

Aportación de las técnicas moleculares al diagnóstico de "citomegalovirus" en el receptor de trasplante alogénico de progenitores

Manuel López-Brea Calvo

12

Casanova Fernández, Lucía

Papel de la Quinasa Inductora de NF-kB en el trasplante hematopoyético.

Manuel Ramírez Orellana

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Cruz Adalia, Arantxa

La molécula de activación leucocitaria CD69 como regulador de los procesos inflamatorios

Francisco Sánchez Madrid

1

De la Fuente Martín, Esther

Implicación de los astrocitos hipotalámicos en las alteraciones metabólicas y en los cambios de composición corporal inducidos por malnutrición en los periodos neonatal y adulto: nuevas acciones de la leptina y la ghrelina

Jesús Argente Oliver, Julie Ann Chowen King

26

García Cáceres, Cristina

Cambios morfológicos y funcionales de los astrocitos hipotalámicos en las alteraciones metabólicas centrales y periféricas inducidas por una dieta rica en grasa durante la etapa prenatal y postnatal.

Jesús Argente Oliver, Julie Ann Chowen King

Martínez Laperche, Carolina

Estudio de la infiltración del sistema nervioso central en niños con leucemia linfoblástica aguda y el papel de BMP4

Manuel Ramírez Orellana

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Martorell, Almudena

La salud mental en la discapacidad intelectual: un recorrido de interrelaciones

José Luis Ayuso Mateos

33

Pérez de José, Ana

Fallo renal agudo en la cirugía cardiaca.

Carmen Bernis Carro

21

Sreeramkumar, Vinatha

Role of Prostaglandin E2 in T cell activation and migration

Manuel Fresno Escudero, Natalia Cuesta Rubio, Federico Mayor Menéndez

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Trullats Vila, Joan Carles

Enfermedad Renal Crónica y terapia renal sustitutiva en pacientes con infección por el virus de la inmunodeficiencia humana. Prevalencia y supervivencia

Guillermina Barril Cuadrado

Papel Del Receptor Cannabinoide Tipo 2 En Procesos De Neuroprotección y Neurorreparación Tras La Isquemia Cerebral Experimental

María Ángeles Moro Sánchez, Ignacio Lizasoain Hernández, María Encarnación Fernández

Zarruk Serrano, Juan Guillermo

26

21

Associated 1, 38

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Summary

GUIDELINES Area 1: Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases Line 7: Inflammatory mechanisms in pulmonary diseases Group 22 Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 183(6): 788824. 2011. PMID: 21471066.

Area 2: Neurotransmission, Pharmacological Neuroprotection and Neurodegenerative and Neuropsychiatric diseases Line 4: Diagnostic and therapeutic advances in affective disorders Group 33 International Experts: Clive Adams, Reino Unido; Robert Ali, Australia; Alan Apter, Israel; Yael Apter, Israel; José Ayuso-Mateos *, España; Corrado Barbui *, Italia; Erin Barriball, Australia; Ettore Beghi, Italia; Gail Bell, Reino Unido; Gretchen Birbeck *, Estados Unidos; Jonathan Bisson, Reino Unido; Philip Boyce, Australia; Vladimir Carli, Suecia; Erico Castro- Costa, Brasil; Andrew Mohanraj Chandrasekaran §, Indonesia; Sonia Chehil, Canadá; Colin Coxhead, Suiza; Jair de Jesus Mari, Brasil; Carlos de Mendonça Lima, Portugal; Diego DeLeo, Australia; Christopher Dowrick, Reino Unido; Colin Drummond, Reino Unido; Julian Eaton §, Nigeria; Eric Emerson, Reino Unido; Cleusa P Ferri, Reino Unido; Alan Flisher †*, África del Sur; Eric Fombonne, Canadá; Maria Lucia Formigoni §, Brasil; Melvyn Freeman *, África del Sur; Linda Gask, Reino Unido; Panteleimon Giannakopoulos *, Suiza; Richard

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P Hastings, Reino Unido; Allan Horwitz, Estados Unidos; Takashi Izutsu, Fondo de Población de las Naciones Unidas; Lynne M Jones §, Reino Unido; Mario F Juruena, Brasil; Budi Anna Keliat §; Indonesia; Kairi Kolves, Australia; Shaji S Kunnukattil §, India; Stan Kutcher, Canadá; Tuuli Lahti, Finlandia; Noeline Latt, Australia; Itzhak Levav *, Israel; Nicholas Lintzeris, Australia; Jouko Lonnqvist, Finlandia; Lars Mehlum, Noruega; Nalaka Mendis, Sri Lanka; Ana-Claire Meyer, Estados Unidos; Valerio Daisy Miguelina Acosta, República Dominicana; Li Li Min, Brazil; Charles Newton §, Kenia; Isidore Obot *, Nigeria; Lubomir Okruhlica§, Eslovaquia; Olayinka Omigbodun *§, Nigeria; Timo Partonen, Finlandia; Vikram Patel *, India y Reino Unido; Michael Phillips *§, China; Pierre-Marie Preux, Francia; Martin Prince *§, Reino Unido; Atif Rahman *§, Pakistán y Reino Unido; Afarin RahimiMovaghar *, Irán; Janet Robertson, Reino Unido; Josemir W Sander *, Reino Unido; Sardarpour Gudarzi Shahrokh, Irán; John Saunders *, Australia; Chiara Servili §, Italia; Pratap Sharan §, I ndia; Lorenzo Tarsitani, Italia; Rangaswamy Thara *§, India; Graham Thornicroft *§, Reino Unido; Jürgen Ünutzer *, Estados Unidos; Mark Vakkur, Suiza; Peter Ventevogel *§, Holanda; Lakshmi Vijayakumar *§, India; Eugenio Vitelli, Italia; Wen-zhi Wang §, China. MhGAP Intervention Guide for mental, neurological and substance use disorders in non-specialized health settings. World Health Organization Press. 2011. Entidad: Organización Mundial de la Salud. ISBN: 978-92-4-354806-7. Javier Jiménez Pietropaolo, Silvia Martín Ulloa,Teresa Pacheco Tabuenca, José Luís Pérez-Iñigo Gancedo, José Ignacio Robles Sánchez, Paloma Santiago García, Andrés Torras García, José Luís Ayuso Mateos, Francisco Rodríguez Pulido, Guillermo Petersen Guitarte. Guía para familiares. Detección y prevención de la conducta suicida. Comunidad de Madrid. Dirección General de Hospitales. 2011. Entidad: Comunidad de Madrid. Disponible online. http://www.madrid.org /cs/Satellite?c=CM_Publicaciones_FA&cid=114266296 5405&idConsejeria=1109266187266&idListConsj=110 9265444710&idOrganismo=1142439319720&languag e=es&pagename=ComunidadMadrid%2FEstructura& sm=1109266101003.

Summary

Dua T, Barbui C, Clark N, Fleischmann A, Poznyak V, van Ommeren M, Yasamy MT, Ayuso-Mateos JL, Birbeck GL, Drummond C, Freeman M, Giannakopoulos P, Levav I, Obot IS, Omigbodun O, Patel V, Phillips M, Prince M, Rahimi-Movaghar A, Rahman A, Sander JW, Saunders JB, Servili C, Rangaswamy T, Unützer J, Ventevogel P, Vijayakumar L, Thornicroft G, Saxena S. Evidence-Based Guidelines for Mental, Neurological, and Substance Use Disorders in Low- and MiddleIncome Countries: Summary of WHO Recommendations. PLoS Med 8(11):e10011. 2011. PMID: 22110406.

Area 3: Advanced therapies and individualized medicine. Line 1: Prognostic and predictor markers in autoimmune diseases Group 36 Pérez Edo L, Alonso Ruiz A, Roig Vilaseca D, García Vadillo A, Guañabens Gay N, Peris P, Torrijos Eslava A, Beltrán Audera C, Fiter Aresté J, Arboleya Rodríguez L, Graña Gil J, Carbonell Abelló J, Nolla JM, Holgado Pérez S, Salas Heredia E, Zubieta Tabernero J, Del Pino Montes J, Blanch i Rubió J, Caamaño Freire M, Rodríguez Pérez M, Castañeda S, Cerdá D, Gómez Vaquero C, Calvo Catalá J, Ciria M, Loza E. 2011 Update of the consensus statement of the Spanish Society of Rheumatology on osteoporosis. Reumatol Clin. 7(6):357-79. Epub 2011 Sep 15. 2011. PMID: 22078694. Gómez Reino J, Loza E, Andreu JL, Balsa A, Batlle E, Cañete JD, Collantes Estévez E, Fernández Carballido C, Fernández Sueiro JL, García de Vicuña R, GonzálezÁlvaro I, González Fernández C, Juanola X, Linares LF, Marenco JL, Martín Mola E, Moreno Ramos M, Mulero Mendoza J, Muñoz Fernández S, Queiro R, Richi Alberti P, Sanz J, Tornero Molina J, Zarco Montejo P, Carmona L. Consensus statement of the Spanish Society of Rheumatology on risk management of biologic therapy in rheumatic patients. Reumatol Clin. 7(5):284-98. Epub 2011 Aug 4. 2011. PMID: 21925444. Juanola Roura X, Zarco Montejo P, Sanz Sanz J, Muñoz Fernández S, Mulero Mendoza J, Linares Ferrando LF,

Gratacós Masmitja J, García de Vicuña R, Fernandez Carballido C, Collantes Estevez E, Batlle Gualda E, Ariza Ariza R, Loza Santamaría E. Consensus Statement of the Spanish Society of Rheumatology on the management of biologic therapies in spondyloarthritis except for psoriatic arthritis. Reumatol Clin. 7(2):113-123. Epub 2011 Feb 22. 2011. PMID: 21794794. doi: 10.1016/j.reuma.2010.12.002. C Jose Luis Fernández Sueiro, Xavier Juanola Roura, Juan de Dios Cañete Crespillo, Juan Carlos Torre Alonso, Rosario García de Vicuña, Rubén Queiro Silva, Rafael Ariza Ariza, Enrique Batlle Gualda, Estíbaliz Loza Santamaría. Consensus statement of the Spanish Society of Rheumatology on the management of biologic therapies in psoriatic arthritis. Reumatol Clin. 7(3):179-88. Epub 2011 Mar 21. 2011. PMID: 21794810. Panelistas: José Luis Andréu Sánchez, Alejandro Balsa Criado, Enrique Batlle Gualda, Federico Díaz González, Ángel Elena Ibáñez, Mariano Tomás Flórez García, Fernando García Pérez, Nuria Guañabens Gay, César Hernández García, Mª Victoria Irigoyen Oyarzabal, José Luis Marenco de la Fuente, Víctor Manuel Martínez Taboada, José María Salazar Vallinas, Alejandro Tejedor Varillas, Juana de la Torre Aboki. Coordinadores: Pablo Lázaro de Mercado, Mª Dolores Aguilar Conesa, Loreto Carmona, Revisores: Ana Ortiz García, Antonio Fernández Nebro, Blanca Hernández Cruz, Cayetano Alegre de Miquel, Claudia Alejandra Pereda Testa, Eugenio Chamizo Carmona, Jesús Maese, José de la Mata Llord, Ramón Esteban Mazzucchelli, Lydia Abásolo Alcázar, Mª Betina Nishishinya, Mª Rosa González Crespo, Miguel Ángel Abad Hernández, Santiago Muñoz. Guía de práctica clínica para el manejo de la Artritis Reumatoide. GUIPCAR. 2011. Entidad: Sociedad Española de Reumatología. http://www.ser.es/ArchivosDESCARGABLES/Proyectos /GUIPCAR_2007/GUIPCAR2007-Completa.pdf Última actualización 2011 en: http://www.ser.es/practicaClinica /GUIPCAR_2007/Metodologia/Menu1_Metodologia_Ac tualizacion_I5.php. Group 37 Carrascosa JM, López-Estebaranz JL, Carretero G, Daudén E, Ferrándiz C, Vidal D, Belinchón I, Sánchez-

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Summary

Regaña M, Puig L; Group Español de Psoriasis de la Academia Española de Dermatología y Venereología. Narrowband UV-B, monochromatic excimer laser, and photodynamic therapy in psoriasis: a consensus statement of the Spanish Psoriasis Group. Actas Dermosifiliogr. 102(3):175-86. 2011. PMID: 21310368. Mrowietz U, Kragballe K, Reich K, Spuls P, Griffiths CE, Nast A, Franke J, Antoniou C, Arenberger P, Balieva F, Bylaite M, Correia O, Daudén E, Gisondi P, Iversen L, Kemény L, Lahfa M, Nijsten T, Rantanen T, Reich A, Rosenbach T, Segaert S, Smith C, Talme T, Volc-Platzer B, Yawalkar N. Definition of treatment goals for moderate to severe psoriasis: a European consensus. Arch Dermatol Res. 303(1):1-10. Epub 2010 Sep 21. 2011. PMID: 20857129.

Line 2: Esophagogastrointestinal inflammatory diseases Group 38 J.P. Gisbert. Guía de Práctica Clínica sobre Dispepsia. 2011. Desarrollado conjuntamente por la Asociación Española de Gastroenterología (AEG), la Sociedad Española de Medicina de Familia y Comunitaria (semFYC) y la Colaboración Centro Cochrane Iberoamericano. J. P Gisbert: Revisor y coordinador de Aparato Digestivo. JP Gisbert. Revisor y coordinador. Current concepts in the management of Helicobacter pylori infection: the Maastricht IV Consensus Report. 2011. Entidad: European Helicobacter Study Group. 2010-2011. Group Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) y desarrollado junto con la Colaboración Cochrane. JP Gisbert Coordinador (20072011). Guías de Práctica Clínica en Enfermedad Inflamatoria Intestinal (incuyendo la Guía de colitis ulcerosa, de enfermedad de Crohn y de enfermedad perianal). 2011. J.P. Gisbert Revisor y Coordinador (2010-2011). Proyecto AHEAD2010 (Optimización del uso de inmunosupresores y esteroides en la enfermedad de Crohn). 2011. Entidad: GETECCU. Avalado por GETECCU. J.P. Gisbert. Algoritmos de tratamiento de la anemia ferropénica en enfermedades digestivas con hierro intravenoso. 2011. J.P. Gisbert: Revisor general y Coordinador del tema “Papel del hierro intravenoso en la hemorragia digestiva aguda”.

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Line 3: Progenitors and cell therapy Group 39 Aguado JM, Ruiz-Camps I, Muñoz P, Mensa J, Almirante B, Vázquez L, Rovira M, Martín-Dávila P, Moreno A, Alvarez-Lerma F, León C, Madero L, Ruiz-Contreras J, Fortún J, Cuenca-Estrella M; Group de Estudio de Micología Médica de la SEIMC (GEMICOMED). Guidelines for the treatment of Invasive Candidiasis and other yeasts. Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). 2010 Update. Enferm Infecc Microbiol Clin 29(5): 345-361. 2011. PMIP: 21459489.

Line 7: New therapies in infectious pathologies Group 50 Fortun J, Carratala J, Gavalda J, Lizasoain M, Salavert M, de la Camara R, Borges M, Cervera C, Garnacho J, Lassaleta A, Lumbreras C, Sanz MA, Ramos JT, TorreCisneros J, Aguado JM, Cuenca-Estrella M. Guidelines for the Treatment of Invasive Fungal Disease by Aspergillus spp. and Other Fungi Issued by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). 2011 Update. Enfermedades infecciosas y microbiologia clinica. 29(6):435-54. 2011. PMID: 21474210. Jesús Sanz Sanz, entre otros miembros del panel de expertos. Documento de consenso de Gesida/Plan Nacional sobre el Sida sobre el tratamiento antirretroviral del adulto. www.gesidaseimc.org. 2011. Entidad: Gesida / PNS. Group 51 Blanquer J, Aspa J, Anzueto A, Ferrer M, Gallego M, Rajas O, Rello J, Rodríguez de Castro F, Torres A. SEPAR Guidelines for Nosocomial Pneumonia. Arch Bronconeumol. 47(10):510-520. Epub 2011 Sep 9. 2011. PMID: 21908091. doi: 10.1016/j.arbres.2011.05.013.

Line 8: Individualized medicine in solid tumours Group 54 Cerezo L, Martin M. Guía Clínica del Cáncer de Canal Anal. Guías clínicas en Oncología Radioterápica sobre Tumores Digestivos: 171-190. 2011. Entidad: Sociedad

Summary

Española de Oncología Radioterápica. ISBN: 978-8492977-09-3. Group 55 Freixinet Gilart J, Hernández Rodríguez H, Martínez Vallina P, Moreno Balsalobre R, Rodríguez Suárez P; SEPAR. Guidelines for the diagnosis and treatment of thoracic traumatism. Arch Bronconeumol. 47(1):41-9. Epub 2010 Dec 28. 2011. PMID: 21190767.

Moreno Balsalobre R, Moreno Mata N, Ramos Izquierdo R, Aragón Valverde FJ, Molins López-Rodo L, Rivas de Andrés JJ, García Fernández JL, Cañizares Carretero MÁ, Congregado Loscertales M, Carbajo Carbajo M; SEPAR. Guidelines on surgery of the thoracic sympathetic nervous system. Arch Bronconeumol. 47(2):94-102. Epub 2011 Feb 20. 2011. PMID: 21342743.

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Summary

PATENTS During 2011 three new patent applications have been filed by researchers from our Institute and four new

patents have been granted. Information about these patents is summarized below.

Patents applied for

TITTLE

AUTHOR

APPLICATION NUMBER

GROUP

Composición farmacéutica para el tratamiento de las enfermedades cerebrovasculares

Lizasoain I, Moro MA, Hurtado O, Pradillo J

201101263

Associated 1

Uso de una composición en la elaboración de una solución de diálisis para el tratamiento de las enfermedades cerebrovasculares mediante diálisis peritoneal

Moro MA, Lizasoain I, Sánchez-Prieto J, Torres M, Godino MC, Sobrado M, González VM, Vivancos J

201100829

Associated 1 35

Péptido inhibidor de p38 y aplicaciones

F. Mayor, Jr., C. Murga, P. Campos, J. Heijnen, A. Kavelaars, A. Morreale

201131754

11

APPLICATION NUMBER

GROUP

Patents granted

TITTLE

AUTHOR

Uso de cepas de Leishmania DHSP70-II como vacuna

Carrión, J., Folgueira, C., Fresno, M. & Requena, J.M

200900387

12

Método de obtención de datos útiles para el diagnóstico de neoplasias de células T

Piqueras, J.F., Hernández, S., Villa-Morales, M, González-Sanchez, Laura, Fresno, M. & Fernández-Navarro

200900084

12

Uso de derivados de 3-fenilcumarinas 6-sustituídas y preparación de nuevos derivados

Santana L, Orallo F, Viña D, Correia MJ, Quezada E, Yáñez M, Vilar S, Uriarte E

200900224

3

Lipopolysaccharide of ochrobactrum intermedium and their use as immunostimulant of mamalians

Ovejero Guisasola, Juan Ignacio y Fresno Escudero, Manuel

200930265

12

14 – – 14

AREA 1

CELLULAR AND MOLECULAR ETIOPATHOGENIC MECHANISMS IN INFLAMMATORY AND AUTOIMMUNE DISEASES

Line 1.1

Intercellular Communication in the Inflammatory Response.

Line 1.2

Cellular and molecular responses to Hypoxia.

Line 1.3

Animal models of inflammatory diseases and intercellular signalling.

Line 1.4

Etiopathogenic and immunological mechanisms of dermatological diseases.

Line 1.5

Cellular mechanisms and molecular determinants of allergy-based diseases.

Line 1.6

Inflammatory processes in nephrological diseases.

Line 1.7

Inflammatory mechanisms in pulmonary diseases.

Line 1.8

Inflammatory response in hepatic diseases.

Line 1.9

Mechanisms and mediators of endocrine diseases.

Line 1.10

Children´s development (obesity and growth).

Line 1.11

Metabolic syndrome and vascular risk.

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AREA 1 CELLULAR AND MOLECULAR ETIOPATHOGENIC MECHANISMS IN INFLAMMATORY AND AUTOIMMUNE DISEASES

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AREA 1 CELLULAR AND MOLECULAR ETIOPATHOGENIC MECHANISMS IN INFLAMMATORY AND AUTOIMMUNE DISEASES

Line 1.1 Intercellular Communication in the Inflammatory Response GROUP 1 HEAD OF LABORATORY Francisco Sánchez-Madrid. Scientific Director, Inmmunology.

• • • • • • • •

Isabel María Olazábal Olarreaga Manuel Pérez Martínez Marta Esther Ramírez Huesca Javier Robles Valero Vera Rocha Perugini Mónica Sala Valdés Emilio Tejera Puente Mª Ángeles Ursa Pecharromán

RESEARCH INTEREST

GROUP MEMBERS • Francesc Baixauli Celda • Olga Barreiro del Río • Marta Barrero Villar • José Román Cabrero García • Hortensia de la Fuente Flores • Manuel Gómez Gutiérrez • Cristina Gutiérrez Vázquez • María José López Campos • Noa Beatriz Martín Cófreces • Gloria Martínez del Hoyo Cañizares • Adela Matesanz Marín • María Mittelbrunn Herrero

A key goal is to define how the microtubule-organizing complex (MTOC), by controlling cytoskeletal rearrangements at the immune synapse (IS), provides a mechanism for macromolecular transport and the concentration of signaling molecules during synaptic contact. In this regard, the role of Mitochondria in organizing the IS has been analyzed. This research program has the potential to reveal how transfer of microRNA between the T cell and the cognate antigen-presenting cell (APC) regulates the early initiation of immunity. The specific transfer of microRNA to the APC through exosomes produced by the T cell during the formation of the IS has been identified. We are also developing methodologies for the in vivo imaging of immune cell infiltration, the inflammatory response and the role of immunoregulatory molecules (CD69, galectins and tetraspanins) in animal models of inflammation and human diseases. Thus, CD69 has been identified as a modulator of sphingo-

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AREA 1

The group’s present work focuses on key cell-to-cell communication events during cognate immune interactions. The study of immune cell activation and differentiation during different physiological and pathological situations has been performed ex vivo in samples from patients and healthy donors, as well as in vitro in cellular samples of antigen- and superantigen-specific immune synapses and in vivo in animal models.

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

sine-1-phosphate-induced migration of skin dendritic cells. Our current specific objectives are the following: 1. To assess the role of MTOC polarization as a signaling and structural platform for the control of secretion during IS formation. 2. To investigate the mechanisms and functional consequences of intercellular transfer of microRNA via the IS. 3. To image immune-inflammatory responses in vivo in order to define the role of immunoregulatory molecules in autoimmune inflammatory diseases.

MAJOR GRANTS • Francisco Sánchez Madrid. Regulation of immune inflammatory responses: Adhesive platforms and regulatory molecules in leukocyte-endothelial and T lymphocyte-dendritic cell interactions, and the mechanism of MTOC translocation during T cell activation. Ministerio de Educación y Ciencia (SAF). SAF 2008-02635. • Francisco Sánchez Madrid. Un abordaje multidisciplinario para el estudio de las células dendríticas derivadas de la médula ósea: Aspectos básicos y clínicos (FONCICYT, Proyecto EU-México). Proyecto EU-México FONCICYT. FONCICYT-C002-2008-1 ALA/127249 • Francisco Sánchez Madrid. Molecular and Cellular mechanisms in Chronic Inflammatory and Autoimmune diseases (MEICA). Genoma España. MEICA. • Francisco Sánchez Madrid. Red temática de enfermedades cardiovasculares (RECAVA). ISCIII. RD060014-0030. • Francisco Sánchez Madrid. Plataforma de análisis genético y proteínas. ISCIII. PI2010/03659.

PUBLICATIONS (12) [IF: 74,629] T cells transfer microRNA-loaded exosomes to antigen presenting cells. The image shows confocal microscopy detection of the exosomal marker CD63-GFP (green) on the surface of recipient APCs (Raji) after incubation with J77-CD63-GFP exosomes. CD45 is stained red and nuclei are blue.

Lamana A, Martin P, de la Fuente H, Martinez-Muñoz L, Cruz-Adalia A, Ramirez-Huesca M, Escribano C, Gollmer K, Mellado M, Stein JV, Rodriguez-Fernandez JL, Sanchez-Madrid F, Del Hoyo GM. CD69 Modulates Sphingosine-1-Phosphate-Induced Migration of Skin Dendritic Cells. J Invest Dermatol. 131(7): 1503-12. 2011. PMID: 21412255. IF: 6,27 Martín P, Sánchez-Madrid F. CD69: An Unexpected Regulator of TH17 Cell-Driven Inflammatory Responses. Sci Signaling 4 (165): pe14. 2011. PMID: 21427408. IF: 6,354

Distribution of dendritic cells in peripheral lymph nodes. Dendritic cells from wild-type (red) and CD69-/- (blue)mice were transferred into C57BL6 recipient mice together with a marker of high endothelial venules (green). Two-photon analysis of draining lymph nodes showed that DCs were mostly located near high endothelial venules and the outer T cell zone inside the lymph node.

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➢ Delgado-Pinar E, Albelda MT, Frías JC, Barreiro O, Tejera E, Kubícek V, Jiménez-Borreguero LJ, SánchezMadrid F, Tóth E, Alarcón J, García-España E. Lanthanide complexes as imaging agents anchored on nano-sized particles of boehmite. Dalton Trans. 40(24): 6451-7. 2011. PMID: 21584297. IF: 3,647

AREA 1 Baixauli F, Martín-Cófreces NB, Morlino G, Carrasco YR, Calabia-Linares C, Veiga E, Serrador JM, SánchezMadrid F. The mitochondrial fission factor dynaminrelated protein 1 modulates T-cell receptor signalling at the immune synapse. EMBO J 30(7): 1238-50. 2011. PMID: 21326213. IF: 10,124 Jean-Mairet RM, López-Menéndez C, SánchezRuiloba L, Sacristán S, Rodríguez-Martínez M, RiolBlanco L, Sánchez-Mateos P, Sánchez-Madrid F, Rodríguez-Fernández JL, Campanero MR, Iglesias T. The neuronal protein Kidins220/ARMS associates with ICAM-3 and other uropod components and regulates T-cell motility. Eur J Immunol 41 (4): 1035-1046. 2011. PMID: 21381019. IF: 4,942 Carmen Calabia-Linares, Manuel Perez-Martinez, Noa Martín-Cofreces, Manuel Alfonso-Pérez, Cristina GutierrezVázquez, María Mittelbrunn, Sales Ibiza, Francisco R. Urbano-Olmos, Covadonga Aguado-Ballano, Carlos Oscar Sánchez-Sorzano, Francisco Sanchez-Madrid and Esteban Veiga. Endosomal clathrin drives actin accumulation at the immunological synapse. J Cell Sci 124 (Pt 5): 820-830. 2011. PMID: 21321329. IF: 6,29

J Immunol. 41(12): 22229154. IF: 4,942

3436-3442.

2011.

PMID:

Nuñez-Andrade N, Lamana A, Sancho D, Gisbert JP, Gonzalez-Amaro R, Sanchez-Madrid F, Urzainqui A. Pselectin glycoprotein ligand-1 modulates immune inflammatory responses in the enteric lamina propria. J Pathol 224(2): 212-21. 2011. PMID: 21432853. IF: 7,274 María Mittelbrunn, Cristina Gutiérrez-Vázquez, Carolina Villarroya-Beltri, Susana González,Fátima SánchezCabo, Manuel Ángel González, Antonio Bernad and Francisco Sánchez-Madrid. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigenpresenting cells. Nature Communications 2:282. 2011. PMID: 21505438. IF: 7,396

GROUP 2 HEAD OF LABORATORY Esteban Veiga Chacón

Yáñez-Mó M, Sánchez-Madrid F, Cabañas C. Membrane proteases and tetraspanins. Biochem Soc Trans. 39 (2): 541-546. 2011. PMID: 21428936. IF: 3,989 Cuesta N, Martín-Cófreces NB, Murga C, van Santen HM. Receptors, signaling networks, and disease. Sci Signal. 4(161): mr3. 2011. PMID: 21343616. IF: 6,354

Domínguez-Luis M, Lamana A, Vazquez J, GarcíaNavas R, Mollinedo F, Sánchez-Madrid F, DíazGonzález F, Urzainqui A. The metalloprotease ADAM8 is associated with and regulates the function of the adhesion receptor PSGL-1 through ERM proteins. Eur

AREA 1

Gutiérrez-López MD, Gilsanz A, Yáñez-Mó M, Ovalle S, Lafuente EM, Domínguez C, Monk PN, GonzálezAlvaro I, Sánchez-Madrid F, Cabañas C. The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9. Cell Mol Life Sci 68(19): 3275-92. 2011. PMID: 21365281. IF: 7,047 GROUP MEMBERS • Carmen Calabia Linares • Cruz Adalia, Arantxa • Feo Lucas, Lidia • Ramírez Santiago, Guillermo • Torres Torresano, Mónica

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Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

RESEARCH INTEREST Our group is interested in the molecular and cellular mechanisms allowing the formation of the immunological synapses. To become activated, T-cells must establish cell–cell contact with antigen-presenting cells (APCs). This contact, known as the immune synapse (IS), drives major morphological and functional changes in T-cells, including massive actin rearrangements necessary for productive IS formation. IS serves as a platform for large-scale molecular exchange between the IS forming cells. Multiple cytokines and vesicles, which drive intercellular communication, are released to the synaptic cleft. We showed for the first time that clathrin, present at the Multivesicular Bodies (MVB) membranes is essential for the massive actin polymerization observed at the IS. This finding, observed in cell lines and primary cells, underscore the role of clathrin as a molecular platform for the recruitment of proteins that promote actin polymerization at the interface of T cells and APCs, and is of outstanding relevance not only to Immunologist but also to Cellular Biologists, and scientists in the field of Cellular Microbiology.

Electron micrograph of the contact of a T cell (left) with an antigen presenting cell (APC; right). Arrows indicate multivesicular bodies close to the cell–cell contact.

Currently, we are also carrying on studies on the molecular mechanisms driving pathogen infections and extending these studies to the intimate relation between bacterial and fungal pathogens with the cells of the immune system. We are also exploring the possible therapeutic use of bacterial products able to modify the immunological system.

PUBLICATIONS (3) [IF: 21,692]

Combination fluorescence and phase- contrast image showing an APC-conjugated T cell expressing td- Tomato-tagged clathrin light chain. td-Tomato–LCa (clathrin) is shown in red, endogenous CD3 in green, and the antigen-primed APC in blue; the T cell is not stained.

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Carmen Calabia-Linares, Manuel Perez-Martinez, Noa Martín-Cofreces, Manuel Alfonso-Pérez, Cristina Gutierrez-Vázquez, María Mittelbrunn, Sales Ibiza, Francisco R. Urbano-Olmos, Covadonga AguadoBallano, Carlos Oscar Sánchez-Sorzano, Francisco Sanchez-Madrid and Esteban Veiga. Endosomal clathrin drives actin accumulation at the immunological synapse. J Cell Sci 124 (Pt 5): 820-830. 2011. PMID: 21321329. IF: 6,29 Visvikis O, Boyer L, Torrino S, Doye A, Lemonnier M, Lorès P, Rolando M, Flatau G, Mettouchi A, Bouvard D,

AREA 1 Veiga E, Gacon G, Cossart P, Lemichez E. Escherichia coli producing CNF1 toxin hijacks Tollip to trigger Rac1-dependent cell invasion. Traffic 12(5): 579-590. 2011. PMID: 21291504. IF: 5,278 Baixauli F, Martín-Cófreces NB, Morlino G, Carrasco YR, Calabia-Linares C, Veiga E, Serrador JM, SánchezMadrid F. The mitochondrial fission factor dynaminrelated protein 1 modulates T-cell receptor signalling at the immune synapse. EMBO J 30(7): 1238-50. 2011. PMID: 21326213. IF: 10,124

GROUP 3 HEAD OF LABORATORY María Yáñez Mó

Functional regulation of sheddase ADAM17 by tetraspanins. The sheddase activity of dispersed ADAM17 is stimulated by phorbol esters resulting in the release of the ectodomains of its substrates TNFα and ICAM-1. Recruitment of ADAM17 into CD9-centered TEMs is induced by overexpression or antibody engagement of this tetraspanin, which exerts negative regulation on the ADAM17 sheddase activity, resulting in reduced ectodomain release of TNFα and ICAM-1.

RESEARCH INTEREST During the last year our group has focused its attention on the role of tetraspanin-enriched microdomains (TEM) in the regulation of membrane proteases. Different membrane-bound proteases such as MT1MMP (Yáñez-Mó et al., 2008) or TACE/ADAM-17

Functional regulation of MT1-MMP by tetraspanins. Tetraspanins directly associate with the membrane-anchored metalloproteinase MT1-MMP/ MMP14 in different cell types. Association with tetraspanins regulates the rate of MT1-MMP degradation at lysosomes. At the plasma membrane tetraspanins may function as a molecular link with other transmembrane proteins. Thus, in endothelial cells, CD151 spatiotemporally coordinates MT1-MMP with integrins for extracellular matrix degradation. MT1-MMP subcellular localization is also dependant on its association with CD44, which is in turn shed by the protease, and is also a component of TEMs.

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AREA 1

GROUP MEMBERS • Mónica Gordón Alonso • Soraya López Martín

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

(Gutierrez-López et al., 2011) are included into the specialized platforms that constitute TEM. Insertion into these microdomains directly modulates their enzymatic activity, so that overexpression of the associated tetraspanin results in an inhibition of shedding, while silencing of the expression of the tetraspanin increases proteolysis. Pericellular matrix proteolysis is a central process in cell invasion and migration. Proteolytic shedding of membrane receptors is also one of the fastest ways for changing a cell phenotype; it can switch pericellular signals into systemic or sequester soluble mediators by shedding of their receptors. Thus, shedding inhibitors are currently used as anti-inflammatory drugs, and shedding phenomena are in the etiopathology of diseases such as Alzheimer, cardiac hypertrophy, inflammation, tumor invasion, etc.

tetraspanin CD9. Cell Mol Life Sci 68(19): 3275-92. 2011. PMID: 21365281. IF: 7,047 Ramírez MÁ, Pericuesta E, Yáñez-Mó M, Palasz A, Gutiérrez-Adán A. Effect of long-term culture of mouse embryonic stem cells under low oxygen concentration as well as on glycosaminoglycan hyaluronan on cell proliferation and differentiation. Cell Prolif. 44(1): 75-85. 2011. PMID: 21199012. IF: 2,742

GROUP 56 HEAD OF LABORATORY Ana Carmen Urzainqui Mayayo

MAJOR GRANTS María Yáñez Mó. Plataformas adherentes basadas en microdominios ricos en tetraspaninas y su conexión con el citoesqueleto y vías de señalización intracelulares. Papel en la extravasación leucocitaria y en la presentación de antígeno. ISCIII. PI08/0794

PUBLICATIONS (4) [IF: 20,825] Yáñez-Mó M, Gutiérrez-López MD, Cabañas C. Functional interplay between tetraspanins and proteases. Cell Mol Life Sci. 68(20): 3323-3335. 2011. PMID: 21687991. IF: 7,047 Yáñez-Mó M, Sánchez-Madrid F, Cabañas C. Membrane proteases and tetraspanins. Biochem Soc Trans. 39 (2): 541-546. 2011. PMID: 21428936. IF: 3,989 Gutiérrez-López MD, Gilsanz A, Yáñez-Mó M, Ovalle S, Lafuente EM, Domínguez C, Monk PN, GonzálezAlvaro I, Sánchez-Madrid F, Cabañas C. The sheddase activity of ADAM17/TACE is regulated by the

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GROUP MEMBERS • Rafael González Tajuelo • Alicia Pérez Frías

RESEARCH INTEREST The adhesion receptor PSGL-1, ligand of P-, E- and LSelectins, is responsible of the initial contacts of leukocytes with the activated endothelium and the rolling on the endothelial cells previous to their extravasation to the surrounding tissues at infection or inflammatory foci. In addition to this important function as an adhesion receptor, we have described a new functional role

AREA 1

A) Role of PSGL-1 in dendritic cells interacting with Selectins P and E in the generation of Treg and peripheral tolerance. B) The homeostatic expression of PSGL-1 is controlled by ADAM8. The expression level and modification of PSGL-1 will determine the PSGL-1/Selectin contacts and the immune system activation.

of PSGL-1 in dendritic cells as tolerogenic receptor implicated in the generation of regulatory T cells. Moreover, we have demonstrated in a mice model of ulcerative colitis, that PSGL-1 is implicated in the maintenance of the intestinal tolerance/immunity balance by modulating the immune inflammatory responses in the enteric lamina propria. Our current research is focused in the characterization of autoimmune problems that we have observed in both, PSGL-1 Knock-out and P-Selectin Knock-out mice (KO mice). We are analyzing the autoantibodies

MAJOR GRANTS Ana Carmen Urzainqui Mayayo. Contribución de PSGL1 y sus ligandos (selectinas) en la distribución tisular de las poblaciones de linfocitos y dcs. Estudio del papel de PSGL-1 en tolerancia periférica y en la regulación de respuestas inflamatorias. ISCIII. PI08/0894.

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AREA 1

PSGL-1 plays two important functions during the tethering and rolling of leukocytes: 1) As adhesion receptor, activating the integrins and promoting the firm adhesion and extravasation of leukocytes and 2) As homeostatic receptor, controlling the cytokine production of the leukocytes and, consequently, modulating the immune response.

present in serum, evaluating the histological problems in internal organs and studying different clinical parameters in both KO mice. We are also studying the involvement of PSGL-1 and P-Selectin in the development of different autoimmune diseases in humans, by analyzing the expression of these molecules in patients with different autoimmune diseases. Remarkably, we have recently published the interaction of human PSGL-1 with the metalloprotease ADAM8 and the regulation of PSGL-1 cellular expression and function by the activation of this metalloprotease that has been implicated in the development of some inflammatory diseases such as asthma. We are also studying the possible implications of ADAM8 in the onset and evolution of different human autoimmune diseases.

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

PUBLICATIONS (4) [IF: 18,486] Nuñez-Andrade N, Lamana A, Sancho D, Gisbert JP, Gonzalez-Amaro R, Sanchez-Madrid F, Urzainqui A. Pselectin glycoprotein ligand-1 modulates immune inflammatory responses in the enteric lamina propria. J Pathol 224(2): 212-21. 2011. PMID: 21432853. IF: 7,274 Domínguez-Luis M, Lamana A, Vazquez J, GarcíaNavas R, Mollinedo F, Sánchez-Madrid F, DíazGonzález F, Urzainqui A. The metalloprotease ADAM8

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is associated with and regulates the function of the adhesion receptor PSGL-1 through ERM proteins. Eur J Immunol. 41(12): 3436-3442. 2011. PMID: 22229154. IF: 4,942 Lamana A, Martin P, de la Fuente H, Martinez-Muñoz L, Cruz-Adalia A, Ramirez-Huesca M, Escribano C, Gollmer K, Mellado M, Stein JV, Rodriguez-Fernandez JL, Sanchez-Madrid F, Del Hoyo GM. CD69 Modulates Sphingosine-1-Phosphate-Induced Migration of Skin Dendritic Cells. J Invest Dermatol. 131(7): 1503-12. 2011. PMID: 21412255. IF: 6,27

AREA 1 Line 1.2 Cellular and molecular responses to Hypoxia GROUP 6 HEAD OF LABORATORY Manuel Ortiz de Landázuri Busca

Model showing the involvement of NDUFA4L2 induction by HIF-1alpha in hypoxic adaptation. HIF-1α stabilization by hypoxia up-regulates NDUFA4L2, which inhibits ETC Complex I activity. As a result, oxygen consumption decreases and ROS production is abrogated, thereby allowing cells to adapt to the hypoxic conditions. In contrast, hypoxia decreases NDUFA4 protein levels.

RESEARCH INTEREST 1) Postnatal inactivation of genes implicated in the hypoxia pathway. Inactivation of HIF-1α y HIF2α and VHLA results in embryonic lethality,that we have circumvented by their inactivation in adult mice using floxed alleles in combination with an ubiquitous tamox-

2) Regulation of Mitochondrial function by hypoxia. The fine regulation of mitochondrial function has proved to be an essential metabolic adaptation to fluctuations in oxygen availability. During hypoxia, cells activate an anaerobic switch that favors glycolysis and attenuates the mitochondrial activity. This switch involves the

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AREA 1

GROUP MEMBERS • Bárbara Acosta Iborra • Eduardo Balsa Martínez • Esther Fuertes Yebra • Gemma Muruáis Martínez • Ángel Ordóñez Navadijo • Alicia Vara Vega • Silvia Noemí Vázquez Cuesta

ifen inducible recombinase Cre-er. The functional consequences of their inactivation in adults have been analyzed. Vhl gene inactivation rapidly resulted in a marked splenomegaly and skin erythema, accompanied by renal and hepatic induction of the erythropoietin (Epo) gene, indicative of the in vivo activation of the oxygen sensing HIF pathway. We showed that acute Vhl gene inactivation also induced Epo gene expression in the heart, revealing cardiac tissue to be an extra-renal source of EPO. Indeed, primary cardiomyocytes and HL-1 cardiac cells both induce Epo gene expression when exposed to low O(2) tension in a HIF-dependent manner. Thus, as well as demonstrating the potential of dietary tamoxifen administration for gene inactivation studies in UBC-Cre-ER(T2) mouse lines, this data provides evidence of a cardiac oxygen-sensing VHL/HIF/EPO pathway in adult mice.

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

hypoxia-inducible transcription factor-1 (HIF-1). We have identified a HIF-1 target gene, the mitochondrial NDUFA4L2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2). Our results, obtained employing NDUFA4L2-silenced cells and NDUFA4L2 knockout murine embryonic fibroblasts, indicate that hypoxia-induced NDUFA4L2 attenuates mitochondrial oxygen consumption involving inhibition of Complex I activity, which limits the intracellular ROS production under low-oxygen conditions. Thus, reducing mitochondrial Complex I activity via NDUFA4L2 appears to be an essential element in the mitochondrial reprogramming induced by HIF-1.

E, Fernández-Criado C, Landázuri MO, Aragonés J. Acute Vhl gene inactivation induces cardiac HIF-dependent erythropoietin gene expression. PLoS ONE 6(7): e22589. 2011. PMID: 21811636. IF: 4,411

GROUP 7 HEAD OF LABORATORY Antonio Martínez Ruiz

MAJOR GRANTS • Manuel Ortiz de Landázuri Busca. Red temática de enfermedades cardiovasculares (RECAVA). ISCIII. RD06/0014/0031. • Manuel Ortiz de Landázuri Busca. Sensores de oxigeno: reprogramación metabólica y supervivencia celular. MICINN. SAF2010-14851.

PUBLICATIONS (3) [IF: 26,475] Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordóñez A, Corral-Escariz M, Soro I, LópezBernardo E, Perales-Clemente E, Martínez-Ruiz A, Enríquez JA, Aragonés J, Cadenas S, Landázuri MO. Induction of the mitochondrial NDUFA4L2 protein by HIF-1a decreases oxygen consumption by inhibiting complex I activity. Cell Metab 14(6): 768-779. 2011. PMID: 22100406. IF: 18,207 Aragonés J, Elorza A, Acosta-Iborra B, Landázuri MO. Myeloid hypoxia-inducible factors in inflammatory diseases. Crit Rev Immunol 31(1): 1-13. 2011. PMID: 21395507. IF: 3,857 Miró-Murillo M, Elorza A, Soro-Arnáiz I, Albacete-Albacete L, Ordoñez A, Balsa E, Vara-Vega A, Vázquez S, Fuertes

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GROUP MEMBERS • Pablo Hernansanz Agustín • Alicia Izquierdo Álvarez • Elena Ramos Serrano

RESEARCH INTEREST The research of the group is centred on the study of nonenzymatic post-translational modifications induced by reactive oxygen and nitrogen species, especially cysteine reversible oxidative modifications. We also study their relevance in cell function and pathophysiology, mainly in the molecular and cellular responses to hypoxia. Part of our work is the innovation in proteomic methodologies for analyzing these modifications. In collaboration with Dr. Jesús Vázquez (CBMSO), we have developed a speci-

AREA 1

fic approach for labelling, detecting and quantifying these modifications, simultaneously with protein abundance changes, by employing second-generation proteomic techniques (“shotgun proteomics”, based on LC-MS/MS). We also use the fluorescent derivatization, detection and quantitation in two-dimensional electrophoresis. We have previously described a methodology, called “fluorescence switch”, for detecting S-nitrosylated proteins by this kind of derivatization. We have now used a related method to detect reversibly oxidized cysteines, and we called it “redox fluorescence switch” (RFS).

Schematic of the “redox fluorescent switch” (RFS) technique used to label reversibly oxidized protein cysteines, and example of a two-dimensional electrophoresis showing the oxidized RFS signal (green), total protein staining (red), and merge of both.





• We have applied the RFS to analyze differential reversible cysteine oxidations in the acute response of endothelial cells subjected to hypoxia. We have observed a number of proteins that are oxidized after 2 hours in hypoxia, which is reverted by a 30-minutes re-oxygenation. We have identified some of these proteins, among which we have found several proteins that take part in different protein signalling pathways, as well as metabolic enzymes that could have their function altered. The latter could be part of the acute responses to hypoxia before the transcriptional response by the canonical HIF pathway is initiated.

MAJOR GRANTS • Antonio Martínez Ruiz. Papel de las modificaciones postraduccionales inducidas por especies reactivas de



nitrógeno y oxígeno en la señalización por hipoxia en contextos de fisiopatología cardiovascular. ISCIII. CP07/00143. Antonio Martínez Ruiz. Papel funcional del estrés oxidativo y nitrosativo en grandes sistemas biológicos (consorcio ROSAS – “Reactive Oxygen Species And Systems”). MEC. Consolider-Ingenio 2010. CSD200700020. Antonio Martínez Ruiz. Papel de las especies reactivas de oxígeno y nitrógeno y de las modificaciones oxidativas de proteínas en la respuesta a hipoxia en fisiopatología cardiovascular. ISCIII. PS09/00101. Antonio Martínez Ruiz. Identificación de dianas de Snitrosilación en la estimulación de la neurogénesis endógena. MICINN. PRI-AIBPT-2011-1015. Antonio Martínez Ruiz. Identificación proteómica de proteínas vegetales S-nitrosiladas en la respuesta a auxina. MICINN. PRI-AIBAR-2011-0782.

PUBLICATIONS (5) [IF: 50,354] González R, Cruz A, Ferrín G, López-Cillero P, Fernández-Rodríguez R, Briceño J, Gómez MA, Rufián S, Mata MD, Martínez-Ruiz A, Marin JJ, Muntané J. Nitric oxide mimics transcriptional and post-translational regulation during a-Tocopherol cytoprotection against glycochenodeoxycholate-induced cell death in hepatocytes. J Hepatol 55(1): 133-44. 2011. PMID: 21145864. IF: 9,334

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AREA 1

Overview of classical, less classical and non-classical signaling mechanisms induced by nitric oxide. Non classical pathways (dashed orange lines) include production of NO from nitrite and formation of post-translational modifications, whose main mechanisms and reactions are depicted.

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

Martínez-Ruiz A, Cadenas S, Lamas S. Nitric oxide signaling: classical, less classical and nonclassical mechanisms. Free Radic Biol Med 51(1): 17-29. 2011. PMID: 21549190. IF: 5,707 Leon L, Subramaniam S, Cauvard O, PlenchetteColas S, Paul C, Godard C, Martinez-Ruiz A, Legembre P, Jeannin JF, Bettaieb A. S-Nitrosylation of the Death Receptor Fas Promotes Fas LigandMediated Apoptosis in Cancer Cells. Gastroenterology 140(7): 2009-18, 2018.e1-4. 2011. PMID: 21354149. IF: 12,032 Izquierdo-Álvarez A, Martínez-Ruiz A. Thiol redox proteomics seen with fluorescent eyes: the detection of cysteine oxidative modifications by fluorescence derivatization and 2-DE. J Proteomics 75(2): 329-338. 2011. PMID: 21983555. IF: 5,074 Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordóñez A, Corral-Escariz M, Soro I, López-Bernardo E, Perales-Clemente E, MartínezRuiz A, Enríquez JA, Aragonés J, Cadenas S, Landázuri MO. Induction of the mitochondrial NDUFA4L2 protein by HIF-1a decreases oxygen consumption by inhibiting complex I activity. Cell Metab 14(6): 768-779. 2011. PMID: 22100406. IF: 18,207

GROUP 8 HEAD OF LABORATORY María Josefa Calzada García

GROUP MEMBERS • Raquel Bienes Martínez • María Corral Escariz • Gloria Mateo Jiménez

RESEARCH INTEREST Activated CD47 Promotes Pulmonary Arterial Hypertension Through Suppression of Caveolin-1 Pulmonary arterial hypertension (PAH) is a progressive lung disease characterized by pulmonary vasoconstriction and vascular remodeling leading to increased pulmonary vascular resistance and right heart failure. Loss of nitric oxide (NO) signaling and endothelial nitric oxide synthase (eNOS)-derived oxidative stress are key events in the pathogenesis of PAH yet the mechanisms involved remain incompletely known. Previously it has been shown that activation of the cell receptor CD47 by its ligand thrombospondin-1 (TSP1) inhibits eNOS. We have investigated the role activated CD47 plays in promoting PAH. Our results proved that TSP1-mediated activation of CD47 is increased in experimental and human PAH, and promotes disease by limiting Cav-1 inhibition of dysregulated eNOS. Hypoxia Negatively Regulates Anti-angiogenic and Anti-metastatic PEDF in Melanoma Cells by a HIFIndependent, Autophagy Dependent Mechanism Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor (SERPIN) superfamily, displays a potent anti-angiogenic and anti-metastatic activity in a broad range of tumor types. Melanocytes and low aggressive melanoma cells secrete high levels of PEDF, while its expression is lost in highly aggressive melanomas. In this study, we identify hypoxia as a relevant negative regulator of PEDF in melanocytes and low aggressive melanoma cells. Hypoxia decreased PEDF expression by a posttranslational mechanism involving degradation by autophagy and could therefore contribute to the acquisition of highly metastatic potential characteristic of aggressive melanoma cells. Hypoxia down-regulates the expression of the antiangiogenic protein thrombospondin-1 in a hypoxia

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AREA 1

inducible factor-independent and prolyl hydroxylasesdependent manner in clear cell renal carcinoma cell lines Thrombospondin-1 (TSP-1) is a multifunctional matrix protein with potent antitumor activities due in part to its ability to inhibit angiogenesis. Its expression levels determine the fate of many different tumors and more recently it has been shown that TSP-1 loss contributes to the angiogenic phenotype of renal carcinomas (RCC), however the factors involved in its regulation remain unclear. The results of our investigation indicate that the loss of the von Hippel-Lindau tumor suppressor gene (VHL) and hypoxic conditions contribute to TSP-1 levels in these tumors. Furthermore, this autocrine TSP1 regulation proved to be important in ccRCC cell motility. These data substantiate a regulation pattern for TSP1 in the VHLhypoxia axis that demonstrates to be important for ccRCC cell behaviour. Renal carcinoma cells regulate VCAM-1 expression to overcome the immune response VCAM-1 is an adhesion molecule that belongs to the immunoglobulin’s family and its expression has been mostly assigned to the activated endothelium mediating immune cells adhesion and extravasation.

MAJOR GRANTS • María Josefa Calzada García. TSP1 in Pathophysiology: Role in Renal Cancer and Ischemic Tissue Damage and Regeneration. MICINN. SAF2009-11113. • María Josefa Calzada García. TSP1-CD47 in Promotion of PAH-Associated Vasoconstriction and Vascular Overgrowth. NIH. FOA: PA10-067, period 2011-2015

PUBLICATIONS (2) [IF: 21,229] Martin-Manso G, Calzada MJ, Chuman Y, Sipes JM, Xavier CP, Wolf V, Kuznetsova SA, Rubin JS, Roberts DD. sFRP-1 binds via its netrin-related motif to the Nmodule of thrombospondin-1 and blocks thrombospondin-1 stimulation of MDA-MB-231 breast carcinoma cell adhesion and migration. Arch Biochem Biophys. 509(2): 147-56. Epub 2011 Mar 21. 2011. PMID: 21402050. IF: 3,022 Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordóñez A, Corral-Escariz M, Soro I, LópezBernardo E, Perales-Clemente E, Martínez-Ruiz A,

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AREA 1

CD47 activation promotes PAH through suppressing constitutive Caveolin-1 inhibition of eNOS. Under hypoxia, the CD47 ligand TSP1 is upregualted. On binding with TSP1 the cell receptor CD47 is activated leading to disruption of the constitutive interaction between CD47 and membrane caveolin-1 (Cav-1). This in turn leads to decreased Cav-1 and increased eNOS activity. Monomeric hyperactive eNOS then produces superoxide rather than NO resulting in tissue oxidation and nitration.

However, it is also expressed in healthy renal epithelium and renal carcinomas, and most importantly its expression in these renal carcinomas inversely correlates with tumor malignancy, and therefore more advanced tumors have decreased VCAM-1 levels. Our studies on VCAM-1 regulation in renal cell carcinomas demonstrate that VCAM-1 is significantly down-regulated under hypoxic conditions and also in ccRCC lines lacking VHL. This regulation might be relevant to tumor cell immune evasion in that this molecule elicits immune cell binding and interaction specifically mediated by VCAM-1 expressed in the tumor cells with VLA4 receptor expressed in the immune cells. We are working on the hypothesis that the decrease on VCAM-1 levels may be an adaptive response of tumor cells to escape from the immune system

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

Enríquez JA, Aragonés J, Cadenas S, Landázuri MO. Induction of the mitochondrial NDUFA4L2 protein by HIF-1a decreases oxygen consumption by inhibiting complex I activity. Cell Metab 14(6): 768-779. 2011. PMID: 22100406. IF: 18,207

GROUP 9 HEAD OF LABORATORY Julián Aragonés López (A) Gross appearance of mice upon VHl gene inactivation. Representative images of the erhythema in snouts and paws of Vhlfloxed-UBCCre-ERT2 mice when compared with control Vhlfloxed mice are shown. (B) Body weight under high fat diet conditions upon global Hif1α gene inactivation. Images of a Hif1αfloxed-UBC-Cre-ERT2 and control mice showing reduced adiposity upon Hif1α gene inactivation. gWAT (gonadal WAT) is inidicated with an arrow (upper panel). Increase in body weight of Hif1αfloxed-UBC-Cre-ERT2 and control mice after they were switched to a high fat diet (HFD) (lower panel).

GROUP MEMBERS • Ainara Elorza Peregrina • Glenn Marsboom • Florinda Meléndez Rodríguez • Noelia Sánchez Bolívar • Inés Soro Arnaíz

RESEARCH INTEREST The VHL/HIF oxygen sensing pathway in pathology O2 supply to cells or tissues becomes limited during the development of numerous pathological scenarios such cardiac ischemia, inflammation or expansion of white adipose tissue. Cells respond to these O2 fluctuations by activating the hypoxia-inducible factors HIF-1α and HIF-2α. In our research group we aim to study the in vivo contribution of

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these factors in pathology. We have developed the necessary technology to inactivate in adult mice HIF-1α or HIF-2α (loss of function models) as well as their main repressor VHL leading to a constituive activation of both HIFs (gain of function model). VHL-deficient animals have allowed to induce the HIF system in vivo on adulthood which results in a remarkable erythema possibly associated to peripheral vasodilatation, and importantly to identify the cardiac tissue as a source of extrarenal erythropoietin (EPO) (Miro-Murillo et al. PlosOne 2011) (Figure 1A). The previously recognized cardioprotective ability of EPO indicates that this cardiomyocyte autonomous response is part of the tolerance program against cardiac ischemic episodes. On the other hand (i) animals deficient in HIF-1α have allowed us to determine that HIF1α is essential for development of obesity in murine models associated to a white adipose tissue metabolic reprogramming (Figure 1B) and (ii) animals deficient in HIF2α have allowed to unravel its role in tumor progression and cell autonomous proliferation (manuscript under review in Molecular Cell). Therefore these studies are aimed to unravel the molecular mechanisms by which HIF factors contribute to pathological stage and open new opportunities for therapeutic intervention.

AREA 1 MAJOR GRANTS • Julián Aragonés López. Estudio del papel biológico de los sensores de oxígeno prolina hidroxilasa. MEC. BFU2008-03407/BMC • Julián Aragonés López. Gaining sage on the Epoetins' saga: assessing long term risks and advancing towards better Epoetin driven treatment modalities. European Comission. 282551

Miró-Murillo M, Elorza A, Soro-Arnáiz I, AlbaceteAlbacete L, Ordoñez A, Balsa E, Vara-Vega A, Vázquez S, Fuertes E, Fernández-Criado C, Landázuri MO, Aragonés J. Acute Vhl gene inactivation induces cardiac HIF-dependent erythropoietin gene expression. PLoS ONE 6(7): e22589. 2011. PMID: 21811636. IF: 4,411 Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordóñez A, Corral-Escariz M, Soro I, López-Bernardo E, Perales-Clemente E, MartínezRuiz A, Enríquez JA, Aragonés J, Cadenas S, Landázuri MO. Induction of the mitochondrial NDUFA4L2 protein by HIF-1a decreases oxygen consumption by inhibiting complex I activity. Cell Metab 14(6): 768-779. 2011. PMID: 22100406. IF: 18,207 Aragonés J, Elorza A, Acosta-Iborra B, Landázuri MO. Myeloid hypoxia-inducible factors in inflammatory di-seases. Crit Rev Immunol 31(1): 1-13. 2011. PMID: 21395507. IF: 3,857

GROUP 10 HEAD OF LABORATORY Susana Cadenas Álvarez

GROUP MEMBERS • Andrea Anedda • Elia López Bernardo • Cristina Vaca Sanz

RESEARCH INTEREST Metabolic reprogramming induced by HIF Decreased oxygen concentration has significant effects on gene transcription through activation of hypoxia-inducible factor (HIF), an oxygen dependent transcription factor. HIF activates a number of genes involved in the adaptation of tissues to hypoxia. Hypoxia also modulates the balance between aerobic and anaerobic (glycolytic) energy production on numerous tissues. This metabolic reprogramming induced by HIF includes the diversion of pyruvate away from the mitochondria, increased glucose transport into the cell and increased glycolysis. Another adaptation to reduced oxygen levels is a subunit switch that occurs in Complex IV, whereby the COX41 regulatory subunit is replaced by the COX4-2 isoform. These metabolic responses to hypoxia have adaptive significance in the context of protection against excessive reactive oxygen species production (Figure 1). In collaboration with Dr. M.O. Landázuri, we have studied the effects of hypoxia-induced NDUFA4L2 on oxygen consumption (Figure 2). Our results indicate that hypoxia-induced NDUFA4L2 attenuates mitochondrial oxygen consumption through the inhibition of Complex I activity. This effect prevents excessive intracellular ROS production under low-oxygen conditions.

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AREA 1

PUBLICATIONS (3) [IF: 26,475]

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

UCPs in ischaemia tolerance The uncoupling proteins (UCPs) are mitochondrial inner membrane proteins that belong to the superfamily of mitochondrial anion carriers. Unlike UCP1, which is expressed in brown adipose tissue and that mediates adaptive thermogenesis, the physiological functions of UCP2 and UCP3, two UCP1 homologues present in the heart, remain unclear. We are currently studying the role of these proteins in ischaemia tolerance and the signalling pathways involved.

Regulation of metabolism by HIF. In response to cellular hypoxia, increased HIF-1 activity leads to the following: increased glucose transport into the cell; increased glycolysis and conversion of pyruvate into lactate; decreased conversion of pyruvate into acetyl-CoA (AcCoA); and altered cytochrome c oxidase (COX) subunit composition that maintains efficient electron transport and minimizes superoxide production.

MAJOR GRANTS Susana Cadenas Álvarez. Desacoplamiento mitocondrial en isquemia experimental y clínica. ISCIII. PS09/00116

PUBLICATIONS (2) [IF: 23,907] Martínez-Ruiz A, Cadenas S, Lamas S. Nitric oxide signaling: classical, less classical and nonclassical mechanisms. Free Radic Biol Med 51(1): 17-29. 2011. PMID: 21549190. IF: 5,707 Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordóñez A, Corral-Escariz M, Soro I, LópezBernardo E, Perales-Clemente E, Martínez-Ruiz A, Enríquez JA, Aragonés J, Cadenas S, Landázuri MO. Induction of the mitochondrial NDUFA4L2 protein by HIF-1a decreases oxygen consumption by inhibiting complex I activity. Cell Metab 14(6): 768-779. 2011. PMID: 22100406. IF: 18,20

NDUFA4L2 decreases oxygen consumption in hypoxia. Oxygen consumption rates were measured by high-resolution respirometry in HeLa cells transfected with a scramble control or NDUFA4L2 siRNA (B), or the empty vector (EV) or pCMV-NDUFA4L2 (D), and exposed to hypoxic (1% O2) conditions for 24 h. Data represent mean ± SEM of four independent experiments; *P < 0.05; **P < 0.01

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AREA 1 Line 1.3 Animal models of inflammatory diseases and intercellular signalling GROUP 11 HEAD OF LABORATORY Federico Mayor Menéndez

GRK2 and HDAC6-mediated tubulin deacetylation in epithelial cell migration. In the lamellipodium, GRK2 would be recruited in a Gβγ-dependent manner to sites of the plasma membrane wherein chemotactic activation is taking place. At such specific locations, chemokine receptor stimulation would promote the phosphorylation of GRK2 at S670 by MAPK, what would in turn switch on the ability of GRK2 to phosphorylate co-localized HDAC6. Phosphorylated HDAC6 would display a higher de-acetylase activity toward tubulin at such location, contributing to keep down MT acetylation specifically at the lamellipodium. The presence of highly dynamic, hipoacetylated MTs would stimulate cortical F-actin polymerization and enhance cell migration (adapted from Lafarga V et al., EMBO Journal, 2011)

RESEARCH INTEREST G protein-coupled-receptor kinase 2 (GRK2) is emerging as a key integrative node in many signaling networks. GRK2

displays a complex network of functional interactions (“interactome”) that underlies a variety of novel physiological roles. Changes in GRK2 expression occur in several relevant inflammatory, metabolic, cardiovascular or cancer diseases, suggesting that those alterations may contribute to the development of these pathologies. In order to assess the feasibility of GRK2 as a useful biomarker and/or therapeutic target, our main objectives are the identification of the relevant GRK2 interactome in specific physiopathological contexts and the evaluation of the functional impact of alterations in GRK2 levels using cellular and animal models. During 2011, we have: a) Revealed the existence of multiple scaffolding functions in the degradation of GRK2 by the proteasome pathway, and identified a direct interaction between GRK2 and the Mdm2 E3-ubiquitin ligase (Nogués L et al., J. Biol. Chem. 2011) b) Identified a novel Galpha-q/ PKCzeta/ ERK5 pathway that has an important role in angiotensin-mediated heart

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AREA 1

GROUP MEMBERS • Raúl Alvarado Arroyo • Vanesa Lafarga Berciano • Adolfo Molejón García • Laura Nogués Vera • Julia Palacios García • Petronila Penela Márquez • Paula Ramos Barbeito • Catalina Ribas Núñez • Verónica Rivas Guerrero • Susana Rojo Berciano • Guzmán Sánchez Fernández • Almudena Inés Santos Bajo

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

hypertrophy in vivo (Garcia-Hoz C , Sanchez-Fernández G et al. , J. Biol. Chem. 2012) c) In collaboration with Dr. J. De Celis (CBM Madrid), revealed the participation of Drosophila GRKs and arrestin homologs in the control of the Smoothened signaling pathway (Molnar C et al., Plos Genetics 2011) d) In collaboration with the group of Dr. Cristina Murga (UAM-IISLP), further developed a new type of p38 MAPK inhibitors based on the mechanism of regulation of p38MAPK by GRK2 (two patents filed) e) Also in collaboration with the group of Dr. Cristina Murga (UAM-IISLP), continued investigating the role of GRK2 in obesity and insulin resistance as well as in cardioprotection. f) Discovered that GRK2 modulates tubulin acetylation in a HDAC6-dependent manner in order to regulate key cellular processes relying on cytoskeletal rearrangements such as migration, polarity and cell spreading (Lafarga V et al., EMBO Journal, 2011)

MAJOR GRANTS • Catalina Ribas Núñez. Señalización a través de receptores acoplados a Proteínas G. Interacciones uncionales entre las vías Mapk, G?Q Y GRKS y su relación con enfermedades cardiovasculares. ISCIII. PI080461 • Federico Mayor Menéndez. Quinasas de receptores acoplados a proteínas G: interactoma e implicaciones fisiopatológicas. Ministerio de Ciencia e Innovación. SAF2008-00552

Effect of ionizing radiation in sensory ganglion neurons: organization and dynamics of nuclear compartments of DNA damage/repair and their relationship with transcription and cell cycle. Acta Neuropathol. 122(4): 481-493. 2011. PMID: 21915754. IF: 7,695 Nogués L, Salcedo A, Mayor F Jr, Penela P. Multiple scaffolding functions of {beta}-arrestins in the degradation of G protein-coupled receptor kinase 2. J Biol Chem. 286(2): 1165-1173. 2011. PMID: 21081496. IF: 5,328 Baltanás, F.C., Casfont, I., Lafarga, V., Weruaga, E., Alonso, J.R., Berciano, M.T., and Lafarga, M. Purkinje cell degeneration in pcd mice reveals large scle chromatin reorganization and gene silencing linked to defective DNA repair. J Biol Chem. 286(32): 28287-28302. 2011. PMID: 21700704. IF: 5,328 Aymerich MS, López-Azcárate J, Bonaventura J, Navarro G, Fernández-Suárez D, Casadó V, Mayor F, Lluís C, Valencia M, Artieda J, Franco R. Real-time g-protein-coupled receptor imaging to understand and quantify receptor dynamics. ScientificWorldJournal. 11: 1995-2010. 2011. PMID: 22125451. IF: 1,524 Molnar C, Ruiz-Gómez A, Martín M, Rojo-Berciano S, Mayor F, de Celis JF. Role of the Drosophila non-visual ßarrestin kurtz in hedgehog signalling. PLoS Genet 7(3): e1001335. Epub 2011 Mar 17. 2011. PMID: 21437272. IF: 9,543

GROUP 12 HEAD OF LABORATORY Manuel Fresno Escudero

PUBLICATIONS (6) [IF: 39,542] V. Lafarga, I. Aymerich, O. Tapia, F. Mayor, jr., and P. Penela. A novel GRK3/HDAC6 interaction modulates cell spreading and motility. EMBO J 31(4): 856-69. 2011. PMID: 22193721. IF: 10,124 Casafont I, Palanca A, Lafarga V, Berciano MT, Lafarga M.

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GROUP MEMBERS • Ruth Álvarez Díaz • Beatriz Barrocal López • Isabel M. Chico-Calero • Carlos Chillón Marinas • Natalia Cuesta Rubio

AREA 1 Mª de los Ángeles de Chorro y de Villa-Ceballos Nuria Gironés Pujol Néstor Adrián Guerrero Gutiérrez Alberto Jiménez Buiza María Gema Marín Alberca Cristóbal Moreno Delgado Inés Claire Osma García Carmen Punzón Gálvez Carmen Mª Sánchez-Valdepeñas Villegas Julien Santi-Rocca Konstantinos Stamatakis Andriani

RESEARCH INTEREST Inflammation lies behind many of the most prevalent diseases of the developed countries. We studied the molecular and cellular mechanisms regulating prostanoid synthesis and the function of pathogenrecognition-receptors as Toll-like (TLRs) in inflammation and leukocyte migration and their involvement in Colon Cancer, Obesity, Atherosclerosis, and graft vs. Host Disease (GVHD). We analyzed the expression and regulation of Cyclooxygenases (Cox) and prostaglandin synthases (PGS) in T lymphocytes and macrophages. T cells produce PGF2alfa and PGE2, which via EP2/EP4 receptor control their migration to lymph nodes and the duration of dendritic cell-CD4 T lymphocytes in lymph nodes. Cox-2-deficient monocytes have an impaired ability to adhere to endothelium and to migrate in vitro and in vivo. Nonetheless, in vivo cox-2 selective deficiency in monocytes increases platelet aggregation and atheroma formation.

Figure Blocking of T cell EP receptors reduced the duration of T cell-DC interactions but did not alter the egress phenotype of Th cells from draining LNs during inflammation. (A) Representative graph from a homing assay indicating the ratio of antagonizing PGE2 receptors (EPA)-treated and DMSO-treated CD4+ T cells in draining LNs of mice, 5 hours after immunization. (B) Representative image stack from 30 minute-video recorded during the late phase of T cell activation using an intravital two-photon microscope. Green cells: CFSE-labelled DMSO-treated control CD4+ T cells, blue cells: Cell tracker blue-EPA-treated CD4+ T cells, red cells: Cell tracker orange-stained DCs, pale brown: PNAd labelled HEV. White arrow in the top right panel shows a DMSO treated control CD4+ T cell interacting with a DC. White arrow in the 2nd row, left panel indicates a blue EPA-treated CD4+ T cell in interaction with a DC. (C) Quantitative analysis of T cell-DC interactions in the early and late phases of T cell activation. (D) Histograms showing S1P1 (left panel) and S1P3 (right panel) expression in mouse CD4+ T cells activated in vitro for 72 hours. (E) Percentages of recovered EPA and DMSO-treated cells from draining LNs in the egress assays.

Cox-2/mPGES1 coordinated transcriptional regulation requires NF-kappaB/Egr1 I macrophages and PGE2 act in autocrine fashion to upregulate its own synthesis. Moreover in cancer cells, mPGES1 is induced by EGF also involving Egr-1 and leading to enhanced tumorigenicity. Also Cox-2 is overexpressed in Colon Carcinoma and is induced by Calcineurin/NFAT. Genetic manipulation of this pathway alters growth and metastasis of tumors. NFAT is expressed

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AREA 1

• • • • • • • • • • •

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

in macrophages and dendritic cells and is activated by TLRs through Cot/NIK/PKCzeta pathway-induced phosphorylation. Adipocytes express NFATc1-4 and NFATc4 regulates their differentiation. Trypanosoma cruzi, the agent of Chagas’ disease, has different genetic lineages. We have analyzed the immunopathogenesis, and pathological differences between genetic lineages of T. cruzi. We are analyzing the mechanism of cardiac infiltration by Arginase I-myeloid suppressor cells, Th1, Th2, Th17 and Tregs and its role in cardiac pathology associated to infection and in the modulation of the immune response. We have also investigated the molecular mechanism by which T. cruzi infects myeloid cells. We have defined SLAMF1 as a new receptor for T. cruzi entry and its blockade prevent T. cruzi infection. Slamf1 deficiency or blockade of this receptor completely protects from T. cruzi infection.

MAJOR GRANTS • Manuel Fresno Escudero. Comparative epidemiology of genetic lineages of trypanosoma cruzi-chagasepinet. Project ChagasEpiNet. Unión Europea. HEALTH-FE2008-223034. Seventh Framework Programme • Manuel Fresno Escudero. Inmunopatogenia de la enfermedad de Chagas: nuevas aproximaciones biotecnológicas. Instituto de Cooperación Iberoamericana. A/031735/10 • Manuel Fresno Escudero. Receptores toll-like, prostanoides y redes de señalización en enfermedades inflamatorias. MICINN. SAF2010-18733 • Manuel Fresno Escudero. Estudios para el tratamiento sintomático de la inflamación y el dolor. Neogenius Pharma AIE (Lab Almirall). CENIT-E 2009

Cuervo H, Guerrero NA, Carbajosa S, Beschin A, De Baetselier P, Gironès N, Fresno M. Myeloid-derived suppressor cells infiltrate the heart in acute Trypanosoma cruzi infection. J Immunol. 187(5): 2656-2665. 2011. PMID: 21804013. IF: 5,745 Sreeramkumar V, Fresno M, Cuesta N. Prostaglandin E(2) and T cells: friends or foes?. Immunol Cell Biol. [Epub ahead of print]. 2011. PMID: 21946663. IF: 3,741 Cuesta N, Martín-Cófreces NB, Murga C, van Santen HM. Receptors, signaling networks, and disease. Sci Signal. 4(161): mr3. 2011. PMID: 21343616. IF: 6,354 Alvarez S, Blanco A, Fresno M, Muñoz-Fernández MÁ. TNF-a contributes to caspase-3 independent apoptosis in neuroblastoma cells: role of NFAT. PLoS One. 6 (1): e16100. 2011. PMID: 21298033. IF: 4,411 Alique M, Calleros L, Luengo A, Griera M, Iñiguez MA, Punzón C, Fresno M, Rodríguez-Puyol M, Rodríguez-Puyol D. Changes in extracellular matrix composition regulate cyclooxygenase- 2 (COX-2) expression in human mesangial cells. Am J Physiol Cell Physiol. 300(4): C907-18. 2011. PMID: 21209362. IF: 3,817 Donnini S, Finetti F, Terzuoli E, Giachetti A, Iñiguez MA, Hanaka H, Fresno M, Rådmark O, Ziche M. EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity. Oncogene. 2011 Nov 14. [Epub ahead of print]. 2011. PMID: 22081067. IF: 7,414

GROUP 17 HEAD OF LABORATORY Cristina Murga Montesinos

PUBLICATIONS (7) [IF: 33,612] Carrión J, Folgueira C, Soto M, Fresno M, Requena JM. Leishmania infantum HSP70-II null mutant as candidate vaccine against leishmaniasis: a preliminary evaluation. Parasit Vectors 4: 150. 2011. PMID: 21794145. IF: 2,13

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GROUP MEMBERS • Elisa Lucas Fernández • Rocío Vila Bedmar

AREA 1

RESEARCH INTEREST During the past year 2011, the group has developed the following lines of research: 1) Analysis of the cellular, molecular and systemic mechanisms by which lower levels of GRK2 protect from the development obesity and/or insulin resistance (Vila-Bedmar et al, manuscript under review in The FASEB Journal). Also, we have begun to study the effects that a deletion of GRK2 could have in the progression towards obesity and/or insulin resistance when performed exclusively in determined cell types, or along the development of the pathological condition (In collaboration with the groups of Dr. Federico Mayor and Dr. Cobi Heijnen).

Signaling by Insulin is regulated by GRK2. Recent findings by our group and others have uncovered a negative role for GRK2 protein in the regulation of insulin sensitivity, insulin-dependent metabolic actions, as well as in the control of obesity and adiposity. These effecs of altered GRK2 levels may also affect cardiac cell metabolism in response to insulin.

4) In silico identification of candidate small molecule compounds for p38MAPK based on virtual screening of molecules and peptidomimetic approaches, followed by in vitro validation, and further characterization in cells and in animal models of autoimmune diseases and hyperalgesia. In collaboration with the group of Dr. Federico Mayor.

MAJOR GRANTS

3) Analysis of the vascular response to vasodilatatory and vasoconstrictory neurohumoral stimuli, structure and biomechanics of the vasculature and the development of hypertension by chronic infusion of angiotensin II in mice hemizygous for the GRK2 protein (Lucas E et al, manuscript under preparation in collaboration with the group of Dr. Mercedes Salaíces).

• Cristina Murga Montesinos. Evaluación de compuestos neuroprotectores. Neuron BIOPHARMA, S.L. 409 • Cristina Murga Montesinos. Caracterización de las rutas de señalización de GRK2 y MAPK en hipertrofia y disfunción cardiaca: desarrollo de inhibidores farmacológicos y validación de biomarcadores diagnósticos. UAM. PS09/01208

AREA 1

2) Studies on the gene expression analysis and transcriptional profile of the cardiac tissue of adult (9 months-old) mice hemizygous for GRK2 as well as the status of key cardioprotective signaling routes with age in this mice model. (Lucas E et al, manuscript in preparation in collaboration with the groups of Dr. W.J. Koch and Dr. Javier Díez)

PUBLICATIONS (2) [IF: 11,869] Sorribes A, Armendariz BG, Lopez-Pigozzi D, Murga C, de Polavieja GG. The origin of behavioral bursts in deci-

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Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

sion-making circuitry. PLoS Comput Biol. 7(6): e10020. Epub 2011 Jun 23. 2011. PMID: 21731478. IF: 5,515 Cuesta N, Martín-Cófreces NB, Murga C, van Santen HM. Receptors, signaling networks, and disease. Sci Signal. 4(161): mr3. 2011. PMID: 21343616. IF: 6,354

GROUP 18 HEAD OF LABORATORY Miguel Ángel Iñiguez Peña

GROUP MEMBERS • Cristina Cacheiro Llaguno • Paloma Guillem Llobat • Elena Hernández Subirá • Raquel Nieto Pintado • Ana Renshaw Calderón

RESEARCH INTEREST Several studies have shown that bioactive lipids, including prostanoids and oxysterols, are involved in

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Hypertrophic actions mediated by prostaglandin (PG) F2α in cardiomyocytes involve signalling through its G protein coupled receptor FP and activation of the Ca++/calcineurin/NFAT pathway that promotes transcriptional activation of target genes.

a variety of pathophysiological processes, including vascular homeostasis, inflammation and cardiovascular pathology. Prostanoids family include prostaglandins (PGs) and thromboxanes (TXs), potent lipid mediators derived from arachidonic acid by the action of Cyclooxygenases (COX-1 and COX2) and different PG and TX synthases. These agents are important signalling molecules in an array of physiological processes, besides playing a central role in the progress of the inflammatory reaction associated to a variety of severe diseases. On the other hand, LXRs (Liver X Receptors) and their ligands, including cholesterol derivatives as oxysterols, have been shown to play a key role in the regulation of cholesterol transport and lipid metabolism, being able to act as anti-inflammatory agents through the regulation of gene expression. Our investigations are aimed to the study of the molecular mechanisms involved in the effects of these bioactive lipids, focusing on their influence in cardiovascular pathophysiology. To this end, we analyze the effect of prostanoids, and LXR ligands –mediated signaling, in cell types that play a key role in cardiovascular pathophysiology and the associated inflammatory process as leukocytes, vascular cells, and cardiomyocytes, through the examination of their influence on transcriptional activation and gene expression. In

AREA 1 hypertrophy, atherosclerosis and abdominal aortic aneurysm.

MAJOR GRANTS Miguel Ángel Íñiguez Peña. Mediadores inflamatorios lipídicos en la fisiopatología cardiovascular. MICINN. BFU2010-21055

PUBLICATIONS (2) [IF: 11,231]

addition to cellular models, we are interested in how the effects of these compounds are translated into the context of the cardiovascular pathology by the use of mice models of disease including cardiac

Alique M, Calleros L, Luengo A, Griera M, Iñiguez MA, Punzón C, Fresno M, Rodríguez-Puyol M, Rodríguez-Puyol D. Changes in extracellular matrix composition regulate cyclooxygenase- 2 (COX-2) expression in human mesangial cells. Am J Physiol Cell Physiol. 300(4): C907-18. 2011. PMID: 21209362. IF: 3,817 Donnini S, Finetti F, Terzuoli E, Giachetti A, Iñiguez MA, Hanaka H, Fresno M, Rådmark O, Ziche M. EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity. Oncogene. 2011 Nov 14. [Epub ahead of print]. 2011. PMID: 22081067. IF: 7,414

AREA 1

Abdominal aortic aneurysm (AAA) formation in apoE-/- mice infused with Angiotensin II (AngII) or saline as a control. Left; representative photographs showing aortic dilatation of suprarenal aorta in AAAs of apoE-/- mice infused with AngII. Right; Masson´s trichrome staining of cross sections taken from the suprarenal region of the aorta showing thickening of the abdominal aortic wall, disruption of the media (med) and adventitia (adv) layers, destruction of the elastic lamina, cellular infiltration, extracellular matrix deposition and thrombus formation in mice treated with AngII.

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Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

Line 1.4 Etiopathogenic and immunological mechanisms of dermatological diseases GROUP 19 HEAD OF LABORATORY Amaro García Díez

GROUP MEMBERS • Maximiliano Aragüés Montañés • Javier Fraga Fernández • Silvia Pérez Gala

RESEARCH INTEREST The activity of the Group is focused in the creation of dermatology basic and applied research projects that could answer questions of clinical interest. We are working in several multidisciplinary groups with the collaboration of pathologists, haematologist and immunologist to bring basic research to applied research.

MAJOR GRANTS • Amaro García Díez. Psoriasis y moléculas inmunorreguladoras (GADD-45, ICOSL, trombospondina-1, y galectinas). Sus implicaciones terapéuticas. ISCIII. PI08/0946 • Amaro García Díez. Mecanismos moleculares y celulares en enfermedades inflamatorias crónicas y autoinmunes. Proyecto MEICA. Proyectos de I+D+Ide Cooperación público-privada de Genómica Aplicada y Biotecnología de Genoma España. Genoma España

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Lesional and non-lesional skin from psoriasis patients expresses low levels of gal-1 and IL-10. RT–PCR analysis of the indicated lectin (A) and cytokine (B) genes in non-lesional and lesional skin from psoriasis patients and healthy subjects; expression levels were normalized to GAPDH. Bars represent mean ± SEM from 24 lesional (black), 24 non-lesional (grey) and 10 healthy samples (empty); differences between groups were analysed by the Kruskall–Wallis and Bonferroni tests (∗p < 0.05 compared with healthy). (C) Correlation analysis of gal-1, IL-17 and IL-10 mRNA levels from lesional and nonlesional skin of psoriasis patients; the correlation was tested using the Spearman test.

AREA 1 Santiago-et-Sánchez-Mateos D, Juárez Martín A, González De Arriba A, Delgado Jiménez Y, Fraga J, Hashimoto T, García-Diez A. IgG/IgA pemphigus with IgA and IgG antidesmoglein 1 antibodies detected by enzyme-linked immunosorbent assay: presentation of two cases. J Eur Acad Dermatol Venereol 25 (2): 110-112. 2011. PMID: 20477924. IF: 3,309 Llamas-Velasco M, Argila DD, Eguren C, García-Martin P, Ibañes S, García-Diez A. Solar urticaria unresponsive to intravenous immunoglobulins. Photodermatol Photoimmunol Photomed 27 (1): 53-54. 2011. PMID: 21198885. IF: 1,424

CLINICAL TRIALS

Gal-1, gal-3 and gal-9 are expressed in Langerhans cells in normal skin. (A) Double immunofluorescence analysis of skin from a healthy subject for the expression of gal-1, -3, -7 or -9 (green) and MHC-II (red); nuclei were counterstained with Hoechst (blue); arrowheads mark galectin expression on LCs. (B) Three-colour flow cytometry analysis of galectin expression in DCs isolated ex vivo from the epidermal sheet of normal skin. Cells were gated for HLA-DR expression and galectin expression was then determined on CD1a+ cells.

• Amaro García Díez. Estudio Psoriasis. Schering Plough.

Epidemiológico

PRINCIPAL INVESTIGATOR: AMARO GARCIA DIEZ Asociación de amorolfina al 5% en forma de lca ungueal con itraconazol por vía oral en el tratamiento de las micosis con afectación de la matriz. M04033794 EudraCT: 333 PRINCIPAL INVESTIGATOR: MAXIMILIANO ARAGUES MONTAÑES Estudio fase II de LBH589 oral, en pacientes adultos con linfoma cutáneode células T refractario; (versión final: 2106-06). CLBH589B2201 EudraCT: 2006-000880-27 PRINCIPAL INVESTIGATOR: AMARO GARCIA DIEZ Elaboración y validación de un cuestionario específico de calidad de vida relacionada con la salud (CVRS) en pacientes con urticaria crónica; (versión: 05-07-07). ESTUDIO URQOL

Navarro R, Llamas M, Gallo E, Sánchez-Pérez J, Fraga J, García-Diez A. Follicular mucinosis in a mycosis fungoides-like hypersensitivity syndrome induced by oxcarbamazepine. J Cutan Pathol. 38(12): 1009-11. Epub 2011 Sep 7. 2011. PMID: 21899590. IF: 1,744

PRINCIPAL INVESTIGATOR: AMARO GARCIA DIEZ Estudio post-comercialización observacional, de 10 años de registro de datos de HUMIRA® (Adalimumab) en pacientes adultos con psoriasis crónicaen placas (PS); (versión: 12-03-08). ABBADA-2008-01

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AREA 1

PUBLICATIONS (3) [IF: 6,477]

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

Line 1.5 Cellular mechanisms and molecular determinants of allergy-based diseases GROUP 20 HEAD OF LABORATORY Carlos Blanco Guerra

Serum levels of significant cytokines. Due to distribution patterns, IL-10, IFN-γ and IL-17 are shown as boxplots and TGF-β as mean bars +/- SD. GAA: Gastro-allergic Anisakiasis (acute urticaria), CU+: Anisakis simplex (A. simplex) sensitization associated chronic urticaria, CU-: chronic urticaria without sensitization against A. simplex. (Daschner A. et al., Parasite Immunology 2011).

GROUP MEMBERS • Álvaro Daschner • Consolación de Frutos Moreno • M. Paloma Las Heras Almazán • Tania María Ramos García • Ana Valls Sánchez • Francisco Félix Vega de la Osada

RESEARCH INTEREST Our group has focused on three different research areas throughout 2011: 1) Anisakis simplex allergy: Dr. A. Daschner is leading the project on characterizing Anisakis simplex sensitization

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associated chronic urticaria as a differential phenotype. This project is on its final steps and several contributions are dealing with data on the relationship between fish eating habits, severity of symptoms and search for association with pro- and anti-inflammatory cytokines (Fig 1). Our data are demonstrating that fish intake is not only associated with A. simplex sensitization risk, but also with modulating factors induced by fish-intake per se. Our pluri-disciplinary teaching and research activities in Evolutionary medicine have further contributed to several published papers dealing with new concepts and interpretation of IgE-mediated immune responses associated with parasite-induced allergic phenomena. 2) Food allergy: a new research project, in collaboration with Centro de Biotecnología y Genómica de Plantas (UPM-INIA), is intended to deepen sensitization mechanisms (pre-phase IgE response) to certain plant proteins and the role of different external factors in this process. As a model, we have selected some of the most relevant allergens in food allergy in Spain, such as Pru p 3, a lipid transfer protein from peach.

AREA 1 3) Respiratory allergy: Finally, in the context of the MEICA research project funded by Fundación Genoma España, a phase IV clinical trial is currently being performed, focused on the immunological response to grass pollen specific immunotherapy, in collaboration with ALK and the CNB (Biotechnological National Centre).

MAJOR GRANTS Carlos Blanco Guerra. Mecanismos moleculares y celulares en enfermedades inflamatorias crónicas y autoinmunes. Proyecto MEICA. Proyectos de I+D+I de Cooperación público-privada de Genómica Aplicada y Biotecnología de Genoma España. Genoma España. Proyecto MEICA

PUBLICATIONS (2) [IF: 3,846] Daschner A, Rodero M, De Frutos C, Valls A, Vega F, Blanco C, Cuéllar C. Different serum cytokine levels in chronic vs. acute Anisakis simplex sensitization-associated urticaria. Parasite Immunology 33(6): 357-362. 2011. PMID: 21554330. IF: 2,357 Daschner A, Rodero M, Cuéllar C. Low immunoglobulin E response in gastroallergic anisakiasis could be associated with impaired expulsion of parasite. J Investig Allergol Clin Immunol 21(4): 330-331. 2011. PMID: 21728268. IF: 1,489

CLINICAL TRIALS PRINCIPAL INVESTIGATOR: CARLOS BLANCO GUERRA Mecanismos moleculares y celulares de rinitis alérgica en pacientes tratados con GRAZAX; (versión final: 30-0409). GT-20 EudraCT: 2009-011453-41 PRINCIPAL INVESTIGATOR: CARLOS BLANCO GUERRA Estudio de evaluación de las preferencias y expectativas del paciente en el tratamiento de la alergia con inmunoterapia específica subcutánea; (versión 1: Octubre 2009). ESTUDIO ARIES PRINCIPAL INVESTIGATOR: CARLOS BLANCO GUERRA Estudio abierto para valorar la tolerabilidad de la inmunoterapia con AVANZ Phleum pratense; (versión final: 13-01-11). AV-G-01 EudraCT: 2011-000057-23 PRINCIPAL INVESTIGATOR: CARLOS BLANCO GUERRA Dosis de mantenimiento de AVANZ Phleum pratense; (versión final:29-3-11). AV-G-02 EudraCT: 2011-000120-15 PRINCIPAL INVESTIGATOR: CARLOS BLANCO GUERRA Estandarización biológica del extracto alergénico de Dactylis glomerata para determinar la actividad biológica en unidades equivalentes de Histamina (HEP); (versión 1.0:25-03-11). 6038-PR-PRI-181 EudraCT: 2010-023948-33 PRINCIPAL INVESTIGATOR: CARLOS BLANCO GUERRA Estudio Smile: Satisfacción con el tratamiento y calidad de vida de los pacientes en inmunoterapia sublingual. Creencias y actitudes de los especialistas en su tratamiento; (versión 4.00: 4-7-11). STA-SMI-2011-03 SMI-2011-03

AREA 1

The study aims to be addressed at different levels of complexity: epidemiological, molecular and cellular levels.

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Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

Line 1.6 Inflammatory processes in nephrological diseases GROUP 21 HEAD OF LABORATORY José Antonio Sánchez Tomero

GROUP MEMBERS • Abelardo Isaac Aguilera Peralta • Vicente Álvarez Chiva • Guillermina Barril Cuadrado • Carmen Bernis Carro • Antonio Carlos Fernández Perpén • Martín Giorgi González • Isabel Herráez Jiménez • Pablo Ruano Suárez • Laura Salanova Villanueva • Carmen Sánchez González

RESEARCH INTEREST During 2011 we have continued working in the areas of research previously described. 1) Peritoneal dialysis: we have published two studies analyzing the influence of the new more biocompatible – 46 –

Outcome and Prognostic Factors in HIV-1–Infected Patients on Dialysis in the cART Era: a GESIDA/SEN Cohort Study Joan-Carles Trullas, Federico Cofan, Guillermina Barril, Alberto Martínez-Castelao, Rosa Jofre, Maite Rivera, Jorge Martínez-Ara, Silvia Ros, Iñaki Perez, Asunción Moreno, and Jose M. Miro, the Spanish HIV Infection in Dialysis Study Group. J Acquir Immune Defic Syndr 2011;57:276–283)

dialysis fluids on the conservation of the peritoneal membrane including ex vivo cell cultures and functional studies. Moreover, we have shown that blocking TGF-β1 with specific peptides protects the peritoneal membrane from dialysate-induced damage. 2) We have published a collaborative study analyzing the outcome and prognostic factors in HIV-1 infected patients on dialysis in the cART era. 3) In the field of glomerular diseases we have been involved in a collaborative study to evaluate the clinical value of NPHS-2 analysis in early- and adult-onset

AREA 1 steroid-resistant nephrotic syndrome and published a review of membranous nephropathy in collaboration with Dr Bomback from Columbia University Medical Center to be published shortly by Saunders – Elservier. 4) We participated in a collaborative study on anemia management in kidney transplant patients treated with Methoxy polyethylene glycol-epoetin beta (Mircera). 5. In the field of management in nephrology we have published two papers. A paper that analyzes the number of nephrology residents needed in the near future and another work about the sustainability of treatment renal function replacement in Spain. 5) Finally, we have published a collaborative study, coordinated by the service, which analyzes the opinion of patients on dialysis with respect to end of life and advance care planning.

• Proyecto Coordinado. Repercusiones sistémicas, metabólicas y arterioscleróticas, de los efectos intraperitoneales inducidos por la diálisis peritoneal. Un modelo humano para estudiar la génesis abdominal de la arteriosclerosis. ISCIII. PS-09/00641 • Guillermina Barril Cuadrado. Infección silente por virus C de la hepatitis en unidades de diálisis: análisis de la respuesta inmunoserológica y repercusiones diagnósticas. Fundacion Mutua Madrileña. • Guillermina Barril Cuadrado. Detección del genoma del virus C de la hepatitis en suero de pacientes en diálisis con infección silente por virus C mediante ultracentrifugación y PCR. Fundación Mutua Madrileña. 2551/08 • Guillermina Barril Cuadrado. Supervivencia de los pacientes con infección por el VIH en terapia renal sustitutiva o trasplante renal en España. FIPSE. 24-0858-09 • José Antonio Sánchez Tomero. Estudio de los marcadores de riesgo cardiovascular en la enfermedad renal y proyección pronóstica. Baxter, Palex Nipro.

MAJOR GRANTS PUBLICATIONS (11) [IF: 29,145] Loureiro J, Aguilera A, Selgas R, Sandoval P, Albar-Vizcaíno P, Pérez-Lozano ML, Ruiz-Carpio V, Majano PL, Lamas S, Rodríguez-Pascual F, Borras-Cuesta F, Dotor J, LópezCabrera M. Blocking TGF-B1 protects the peritoneal membrane from dialysate-induced damage. J Am Soc Nephrol 22(9): 1682-1695. 2011. PMID: 21742730. IF: 8,288 Santín S, Tazón-Vega B, Silva I, Cobo MÁ, Giménez I, Ruíz P, García-Maset R, Ballarín J, Torra R, Ars E; FSGS Spanish Study Group (Bernis C). Clinical value of NPHS2 analysis in early- and adult-onset steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 6(2): 344-354. 2011. PMID: 20947785. IF: 4,763 Castillo I, Bartolomé J, Quiroga JA, Barril G, Carreño V. Long-term virological follow up of patients with occult hepatitis C virus infection. Liver Int 31(10): 1519-1524. 2011. PMID: 22093326. IF: 3,84 Bajo MA, Pérez-Lozano ML, Albar-Vizcaino P, del Peso G, Castro MJ, Gonzalez-Mateo G, Fernández-Perpén A, Aguilera A, Sánchez-Villanueva R, Sánchez-Tomero JA, López-Cabrera M, Peter ME, Passlick-Deetjen J, Selgas R. – 47 –

AREA 1

• Abelardo Isaac Aguilera Peralta. Development of a new and more biocompatible peritoneal dialysis solution based in stevioside as osmotic agent. Fresenius Medical Care Deutschland GMBH y Fresenius Medical Care España. IRSIN 1110017 • Abelardo Isaac Aguilera Peralta. Study of the effects of Paricalcitol on the epithelial-to-mesenchymal transition process of mesothelial cells. Abbot. • Abelardo Isaac Aguilera Peralta. Modulación de la transición epitelio mesenquimal (EMT) de las células mesoteliales (CM) como aproximación para mejorar la función peritoneal de pacientes en diálisis peritoneal. ISCIII. FIS: 009/00774 • Abelardo Isaac Aguilera Peralta. Looking for a new, more biocompatible peritoneal dialysis solution based in glicosides as osmotic agent. Fresenius Medical Care. • Abelardo Isaac Aguilera Peralta. Validación de la Transición Epitelio Mesenquimal de Células Mesoteliales como Herramienta para el Diagnóstico y Pronóstico del Fracaso de la Membrana Peritoneal en Pacientes en Diálisis Peritoneal. Sociedad Española de Nefrología. • José Antonio Sánchez Tomero. Mecanismos moleculares que regulan el daño renal provocado por isquemiareperfusión. Amgen SA. IRSIN 2322006

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

Low-GDP peritoneal dialysis fluid ('balance') has less impact in vitro and ex vivo on epithelial-to-mesenchymal transition (EMT) of mesothelial cells than a standard fluid. Nephrol Dial Transplant 26(1): 282-291. 2011. PMID: 20571097. IF: 3,564

alternative for maintaining dialysis treatment. Nefrologia 31(5): 505-513. 2011. PMID: 21959716. IF: 0,738

Trullàs JC, Cofan F, Barril G, Martínez-Castelao A, Jofre R, Rivera M, Martínez-Ara J, Ros S, Perez I, Moreno A, Miró JM; Spanish HIV Infection in Dialysis Study Group. Outcome and prognostic factors in HIV-1-infected patients on dialysis in the cART era: a GESIDA/SEN cohort study. J Acquir Immune Defic Syndr 57(4): 276-283. 2011. PMID: 21623213. IF: 4,262

CLINICAL TRIALS

S. Cigarrán Guldrís, G. Barril Cuadrado. Balance de agua y sodio en diálisis. ¿Qué nos aporta la bioimpedancia?. Nefrologia 2(5 Sup2): 20-24. 2011. PMID: . IF: 0,738

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARRO Estudio multicéntrico prospectivo, doble ciego, controlado con placebo, aleatorizado, de tres grupos paralelos para evaluar la eficacia y seguridad del tratamiento con eritropoyetina recombinante humana en la prevención de la nefrotoxicidad asociada a la utilización de contrastes yodados en pacientes con alto riesgo de disfunción renal. EPOCONT-FRACAM-01 EudraCT: 2007-000994-40

Bernis C, Comisión Nacional de la Especialidad de Nefrología en España. Trends in resident positions offered in nephrology (1985-2008). Nefrología 31(2): 155-161. 2011. PMID: 21461008. IF: 0,738 Salanova Villanueva L, Sánchez González MC, Sánchez Tomero JA, Sanz P. Successful treatment with sodium thiosulfate for calcific uraemic arteriolopathy. Nefrologia 31(3): 366-368. 2011. PMID: 21629345. IF: 0,738 J. Portolés, F. Moreno, P. López-Sánchez, J. Mancha, M. Gómez, E. Corchete, G. del Peso, M.A. Bajo, R. LlópezCarratalá, A. Fernández-Perpén, GROUP Centro de Diálisis Peritoneal (GCDP)*. Peritoneal dialysis and kidney transplant. A two-way ticket in an integrated renal replacement therapy model. Nefrologia 31(4): 441-448. 2011. PMID: 21738247. IF: 0,738

PRINCIPAL INVESTIGATOR: GUILLERMINA BARRIL CUADRADO Efecto de la permeabilidad de la membrana sobre la evolución de los pacientes con IRC (revisión 3.5). MPO STUDY EudraCT: NA

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARRO Estudio observacional retrospectivo para evaluar la variabilidad de los niveles de hemoglobina en pacientes receptores de un trasplante renal con anemia renal crónica; (versión final: 27-09-11). SET-ANE-2011-01 PRINCIPAL INVESTIGATOR: GUILLERMINA BARRIL CUADRADO Estudio sobre las alteraciones del metabolismo oseo y mineral (AMOM) en la Enfermedad Renal Crónica (ERC) en España, (versión final: Noviembre 2008). OSERCE II

Sánchez-Tomero JA, Rodríguez-Jornet A. Balda S, Cigarrán S, Herrero JC, Maduell F, Martín J, Palomar R. Exploring the opinion of CKD patients on dialysis regarding end-of-life and Advance Care Planning. Nefrología 31(4): 449-56. 2011. PMID: 21738248. IF: 0,738

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARRO Estudio observacional retrospectivo para conocer el control de la anemia con metoxi-polietilenglicol epoetina beta en pacientes trasplantados renales; (versión final: 17-08-09). ANEMIA TRANS

Arrieta J, Rodríguez-Carmona A, Remón C, Pérez-Fontán M, Ortega F, Sánchez Tomero JA, Selgas R. GROUP de Apoyo al Desarrollo de la Diálisis Peritoneal en España. Peritoneal dialysis is the best cost-effective

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARRO Efecto del ácido acetilsalicílico en la prevención primaria del riesgo cardiovascular en paciente con enfermedad renal crónica (Estudio AASER); (versión: 02-11-09).

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AREA 1 MG001 EudraCT: 2009-01347-21

mayor/igual 1,78 mmol/l; (versión final 1: 28-1-11). SVCARB06009

PRINCIPAL INVESTIGATOR: JOSE A. SANCHEZ TOMERO Estudio observacional, prospectivo y multicéntrico para establecer un modelo de valoración de la enfermedad aterosclerótica y su valor predictivo de eventos cardiovasculares en pacientes con enfermedad renal crónica en España; (Versión: 1-09-2009). PROYECTO NEFRONA

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARRO Estudio epidemiológico del fracaso renal agudo en la Comunidad de Madrid GEFRAM 2011; (Versión: 30-0311). GEFRAM 2011

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARRO Estudio fase III, multicéntrico, aleatorizado, abierto de grupos paralelos para comparar la eficacia y seguridad de la pauta Prednisona-Ac Micofenólico-Ciclosporina a Prednisona-Ac Micofenólico en el tratamiento de las nefropatias lúpicas tipo III-IV-V; (Versión:1). CSA-LES EudraCT: 2009-017273-38 PRINCIPAL INVESTIGATOR: ANTONIO FERNANDEZ PERPEN Iniciativa para la Evolución Clínica de los Pacientes en Diálisis-DP (Estudio IPOD-PD); (versión final 1.0: 21-05-10). BCM-PD-02-INT PRINCIPAL INVESTIGATOR: GUILLERMINA BARRIL CUADRADO Estudio de observación poscomercialización de Renvela® para vigilar el uso clínico en pacientes adultos hiperfosfatémicos con insuficiencia renal crónica no sometidos a diálisis y con concentraciones séricas de fósforo

PRINCIPAL INVESTIGATOR: JOSE A. SANCHEZ TOMERO Estudio multicéntrico, prospectivo, observacional, para el análisis de factores de progresión de la enfermedad renal crónica en pacientes diabéticos vs no diabéticos. PROGRESER PRINCIPAL INVESTIGATOR: VICENTE ALVAREZ CHIVAS Efecto de paricalcitol sobre la albuminuria, la inflamación y la fibrosis en pacientes con enfermedad renal proteinúrica crónica (Estudio PALIFE): ensayo controlado randomizado, (versión 1.0: 15-06-11). PALIFE-2011-01 EudraCT: 2011-002877-46 PRINCIPAL INVESTIGATOR: JOSE A. SANCHEZ TOMERO Estudio clínico multicéntrico, prospectivo, aleatorizado, abierto y controlado, para la prevención de la infección del orificio externo (IOE) del catéter peritoneal con una pasta antibiótica tópica; (Versión:1 fecha 19/11/2009). PREVIOE-DP EudraCT: 2009-016835-36 PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARRO Estudio piloto: valor pronóstico de la determinación de NGAL en orina al ingreso en la unidad de cuidados intensivos (UCI). NGAL

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AREA 1

PRINCIPAL INVESTIGATOR: GUILLERMINA BARRIL CUADRADO Estudio, abierto multicéntrico, aleatorizado y de 3 grupos paralelos para comparar la eficacia y la seguridad de la carboximaltosa férrica por vía intravenosa (regímenes en dosis bajas y altas de Ferinject®) con las del hierro por vía oral en el tratamiento de la anemia ferropénica en pacientes con nefropatía crónica sin diálisis; (Versión:1 12/08/2009). FER-CKD-01 EudraCT: 2009-015579-28

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARRO Estudio ACERCA: Estudio transversal no intervencionista para evaluar el manejo de la anemia en la enfermedad renal crónica en pacientes no en diálisis, en la práctica clínica diaria, tras las recomendaciones del grupo de trabajo en Anemia-ERBP; (versión final: 04-03-11). SEN-AEE-201101

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

Line 1.7 Inflammatory mechanisms in pulmonary diseases GROUP 22 HEAD OF LABORATORY Julio Ancochea Bermúdez Composition of study groups. LLN = lower limit of normal. Subjects were classified according to the presence of airflow obstruction, which was defined by a postbronchodilator FEV1/FVC ratio of < 0.70 or < LLN obtained from Spanish prediction equations. [23] Subjects were included in the ratio-only group if their FEV1/FVC was < 0.70 but > LLN. Subjects with an FEV1/FVC < LLN were included in the COPD group and stratified into mild or moderate to severe categories according to their predicted FEV1. [6] The remaining subjects were assigned to the non-COPD group.

Hospital in order to investigate the precise role of the Galectins in patients with asthma, as well as their possible implication in the immunopathogenesis of this disease.

GROUP MEMBERS • Carolina Cisneros Serrano • Rosa María Girón Moreno • Ana Martínez Meca • Silvia Sánchez Cuéllar • Enrique Domingo Zamora García

RESEARCH INTEREST Respiratory diseases represent a social and health problem of first order, given its high prevalence and high morbidity and mortality. This group has worked throughout 2011 mainly in Chronic Obstructive Pulmonary Disease (COPD) and Asthma, two highly prevalent respiratory diseases. Asthma is a serious global health chronic problem. We have collaborated with the Immunology Department of the

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The department of Pneumology of La Princesa Hospital participated in 2009 in the project AudiEPOC Spain, where we assessed the quality of care of patients hospitalized for an exacerbation of COPD. In 2011, in order to perform an auditory in Europe about COPD, the European Respiratory Society has created a project that involves 13 countries, including Spain and La Princesa Hospital. In addition to the previous study with COPD patients, the department of Pneumology together with general practitioners has created a project to evaluate two alternatives in the care of patients with COPD: “Healthcare Telemonitoring versus Conventional”. The PROMETE study: “Telemedicine in patients with advanced COPD” aims to evaluate the effectiveness of telemonitoring system, measured by number of exacerbations, hospital admissions and death during the study period in patients with COPD. This project will allow evaluating the quality of life related to the health of these patients comparing two methods.

AREA 1 • Julio Ancochea Bermúdez. Programa de I+D Biomedicina. CONSEPOC-CM. Inflamación e hipoxia: mecanismos de desarrollo y progresión en EPOC y SAHS. Consejería de Educación - CAM.

PUBLICATIONS (7) [IF: 59,007]

Finally, the department of Pneumology of La Princesa Hospital is the only Spanish center that has participated in the new official guidelines for diagnosis and management of Idiophatic Pulmonary Fibrosis elaborated by Internacional Respiratory Societies [(American Respiratory Society (ATS), European Respiratory Society (ERS), Japan Respiratory Society (JRS) and Latin American Thoracic Association (ALAT)].

MAJOR GRANTS • Silvia Sánchez Cuéllar. La implicación del CD69 en la modulación inmune de pacientes asmáticos mediante el análisis de la capacidad de diferenciación de los distintos tipos de células T helper; Th1, Th2 y Th17. ISCIII. SEPAR. • Silvia Sánchez Cuéllar. El papel de las Galectinas como molécula de inmunoregulación en el asma. Neumomadrid. • Julio Ancochea Bermúdez. Desarrollo de nuevas estrategias terapéuticas en la LAM: estudio sobre su origen celular y diseminación. SEPAR.

García-Rio F, Soriano JB, Miravitlles M, Muñoz L, Duran-Tauleria E, Sánchez G, Sobradillo V, Ancochea J. Overdiagnosing subjects with COPD using the 0.7 fixed ratio: correlation with a poor health-related quality of life. Chest. 139(5): 1072-80. Epub 2010 Dec 23. 2011. PMID: 21183609. IF: 6,519 Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE Jr, Lancaster L, Sahn SA, Szwarcberg J, Valeyre D, du Bois RM; Colaborators: Agostini C, Allen J, Andrews C, AntinOzerkis D, Baughman R, Burge S, Chan A, Confalonieri M, Cordier J, Cordova F, Cuomo A, Delaval P, Dhar A, Duarte A, Dushay K, Flaherty K, Frost A, Ginns L, Girod C, Glaspole I, Golden J, Gottfried M, Haller H Jr, Harari S, Helmersen D, Hodder R, Hollingsworth H, Homik L, Khalil N, Kus J, Leonard C, Malouf M, Mette S, Meyer K, Meziane H, Nathan S, Padilla M, Panos R, Pantano J, Patel N, Poletti V, Ramesh W, Richeldi L, Rolf J, Rottoli P, Russell T, Saltini C, Selman M, Shigemitsu H, Sinkowitz D, Stollery D, Strek M, Tino G, Wallaert B, Wells A, Whelan T, Wilcox P, Zibrak J, Ziora D, Zisman D, Acosta O, Ancochea J, Bonnet R, Brantly

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AREA 1

Distribution of overdiagnosed and severity levels of COPD according to sex and age group. The sex and age distribution of the prevalence of overdiagnosed COPD using the fixed ratio and of mild and moderate to severe COPD. The relationship of COPD overdiagnosis with increasing age and male sex can be observed. In addition, the prevalence of overdiagnosed COPD doubles that of mild COPD and becomes even greater in the > 60 age strata.

Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidencebased guidelines for diagnosis and management. Am J Respir Crit Care Med. 183(6): 788-824. 2011. PMID: 21471066. IF: 10,191

Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

M, Chapman J, Davis G, de Andrade J, Doherty D, Egan J, Ettinger N, Fairman P, Geiser T, Gibson K, Habib M, Horiuchi T, Ingrassia T, Kallay M, Landis J, Lasky J, Lorch D, Magnussen H, Morrell F, Morrison L, Musk M, Pfeifer M, Roman J, Rosen G, Sakkhija H, Schaumberg T, Scholand M, Serfilippi G, Slabbynck H, Sussman R, Swigris J, Thomeer M, Thompson A, Verghese G, Wencel M, Wirtz J, Wesselius L, Worth H, Xaubet A, Yagan M, Yung G. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 377(9779): 17601769. 2011. PMID: 21571362. IF: 33,633 Casanova A, Ancochea J. Lymphangioleiomyomato-sis: new therapeutic approaches. Arch Bronconeu-mol. 47(12): 579-580. 2011. PMID: 21924539. IF: 2,166 Miravitlles M, Calle M, Soler-Cataluña JJ, Soriano JB, Ancochea J, Escarrabill J, Almagro P, López D, Marco E, Antonio Riesco J, Antonio Quintano J, Antonio Trigueros J, Molina J, Marzo M, Piñera P, Simón A, Cachinero A, Dolors Navarro M, Llamas M. Moving towards a new focus on COPD. The Spanish COPD Guidelines (GESEPOC). Arch Bronconeumol. 47(8): 379-381. 2011. PMID: 21757283. IF: 2,166 Casanova A, María Girón R, Acosta O, Barrón M, Valenzuela C, Ancochea J. Lymphangioleiomyomatosis treatment with sirolimus. Arch Bronconeumol. 47(9): 470-472. 2011. PMID: 21440356. IF: 2,166 Girón Moreno RM, Salcedo Posadas A, Mar GómezPunter R. Inhaled antibiotic therapy in cystic fibrosis. Arch Bronconeumol. 47(Suppl): 14-18. 2011. PMID: 21703474. IF: 2,166

PRINCIPAL INVESTIGATOR: ROSA-MARIA GIRON MORENO Estudio de la eficacia del tratamiento a largo plazo con suero salino hipertónico sobre las exacerbaciones pulmonares en pacientes con fibrosis quística; (versión 1: 0804-08). SSH-FQ1 EudraCT: 2008-001284-11 PRINCIPAL INVESTIGATOR: ENRIQUE ZAMORA GARCIA AUDIPOC: Auditoría clínica Nacional sobre exacerbaciones de la EPOC en España. PI-07/90516 PRINCIPAL INVESTIGATOR: JULIO ANCOCHEA BERMUDEZ Estudio de extensión de etiqueta abierta de la seguridad a largo plazo de pirfenidona en pacientes con fibrosis pulmonar idiopática (FPI) que completan los estudios CAPACITY; (versión final: 13-12-07). PIPF012 EudraCT: 2007-007800-13 PRINCIPAL INVESTIGATOR: ENRIQUE ZAMORA GARCIA AUDIPOC Europa. COPD ERS PRINCIPAL INVESTIGATOR: ROSA-MARIA GIRON MORENO Prevalencia e impacto de la depresión y la ansiedad en pacientes con fibrosis quística y sus cuidadores. TIDES PRINCIPAL INVESTIGATOR: ROSA-MARIA GIRON MORENO Registro europeo y madrileño de pacientes con Fibrosis Quística. ECFR PRINCIPAL INVESTIGATOR: CAROLINA CISNEROS SERRANO Mejora el tratamiento con CPAP la evolución del asma en pacientes con Síndrome de Apneas-Hipopneas del Sueño?. ESTUDIO CPASMA

CLINICAL TRIALS PRINCIPAL INVESTIGATOR: JULIO ANCOCHEA BERMUDEZ Estudio epidemiológico, prospectivo y multicéntrico de validación de la versión en español del cuestionario CAT (COPD Assesment Test) para EPOC; (versión final: 20-1009). ESTUDIO CAT – 52 –

PRINCIPAL INVESTIGATOR: CAROLINA CISNEROS SERRANO Ensayo clínico fase IIb, aleatorizado, doble ciego para evaluar la eficacia de tralokinumab en pacientes adultos con asma grave no controlada (Versión final:21-06-11). CD-RICAT-354-1049 EudraCT: 2011-001360-21

AREA 1

PRINCIPAL INVESTIGATOR: CAROLINA CISNEROS SERRANO Estudio de la correlación entre los niveles séricos de lgE total y la gravedad del asma en pacientes asmáticos alérgicos en España. Estudio SIGE; (versión final: 17-09-10). NOV-ASM-2010-01

PRINCIPAL INVESTIGATOR: CAROLINA CISNEROS SERRANO Valoración del flujo inspiratorio en el asma bronquial mediante un medidor portátil. Estudio INSPIRA; (versión 2: 2604-10). B-12391005 PRINCIPAL INVESTIGATOR: ROSA-MARIA GIRON MORENO Calidad de vida y trastornos psicológicos en pacientes con bronquiectasias no relacionadas con fibrosis quística; (versión 1.0: 23-09-10). CVPSBQ-10 PRINCIPAL INVESTIGATOR: ENRIQUE ZAMORA GARCIA Frecuencia respiratoria y agudización en la EPOC. FRAEPOC

AREA 1

PRINCIPAL INVESTIGATOR: JULIO ANCOCHEA BERMUDEZ Ensayo clínico aleatorizado, doble ciego, controlado con placebo, de 52 semanas de duración, para evaluar el efecto de 150mg de BIBF 1120 oral, dos veces al día, en la caída anual de la Capacidad Vital Forzada en pacientes con Fibrosis Pulmonar Idiopática; (versión 1 final:06-01-11). 1199.34 EudraCT: 2010-024252-29

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Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases

Line 1.8 Inflammatory response in hepatic diseases GROUP 23 HEAD OF LABORATORY Ricardo Moreno Otero

GROUP MEMBERS • María Jesús Alonso Martín • María Jesús Borque Iñurrita • Luisa Consuelo García Buey • Asunción García Sánchez • Leticia González Moreno • Ángel Hernández Bartolomé • Rosario López Rodríguez • Samuel Martín Vílchez • Jorge Mendoza Jiménez-Ridruejo • Yolanda Real Martínez • Yolanda Rodríguez Muñoz • María Paloma Sanz Cameno • María Trapero Marugán

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RESEARCH INTEREST During last year, our group has been mainly focused on characterizing serum and genetic biomarkers of Chronic hepatitis C (CHC) progression or response to antiviral treatment based on peg-Interferon plus Ribavirin. The inability of the immune system to eradicate the hepatitis C virus (HCV) infection triggers the persistent stimulation of repairing mechanisms, including inflammation, angiogenesis and fibrosis. Therefore, we hypothesised that molecules involved in these processes, such as Angiopoietins/Tie2, might reflect the progression of CHC or the response to treatment. Firstly, the study of angiopoietins serum levels in CHC patients allowed us to formulate an accurate non-inva-

CD16 and Tie-2 expression by peripheral blood monocytes from healthy volunteers and CHC patients. Peripheral blood proportions CD16high and CD16low (A), and Tie-2high and Tie-2low (C) monocytes from control subjects and CHC patients. Relative proportions of CD16high and Tie-2high expressing cells were significantly raised in peripheral blood of CHC patients compared to controls (**p