Web page:
http://departamentos.unican.es/biomol/merino.html
Research lines:
Upon antigenic encounter naïve CD4+ T cells differentiate into distinct functional Th subpopulations with defined patterns of cytokine production and effector functions. Due to their antagonism in the control of lymphoid homeostasis, our interest has been focused in the study of regulatory CD4+CD25+ T cells (Tregs; tolelance) and Th17 cells (involved in the pathogenesis of different autoimmune/inflammatory diseases). Strikingly, both subpopulations are induced after antigenic stimulation in the presence of a common cytokine; TGF. Recent studies show that TGF promotes the generation of Th17 cells together with pro-inflammatory cytokines such as IL-6. In view of the dual role of TGF in the differentiation of Tregs and Th17 and in the antagonistic activity of both populations in the control of immune tolerance, our research is focused in the study of the molecular mechanisms that modulate TGF activity on naïve CD4+ T lymphocytes and that determine the differentiation, functional activity and stability of Tregs and Th17 subpopulations. Those studies are performed using mutant mice that overexpress or are deficient in particular regulators of TGF signalling, in vitro models of Tregs and Th17 differentiation and function and in vivo models of Th17-dependent autoimmune diseases in mice.
In addition, our group is interested in the study of the cause-effect relationship among the development of rheumatoid arthritis and atherosclerosis in experimental animal models of autoimmune arthritis. We are particularly interested in the study of the immunomodulatory properties of ApoE after its overexpression in vivo with lentiviral vectors.
Funding:
Mecanismos moduladores de la diferenciación y actividad funcional de los linfocitos T CD4+CD25+ reguladores. Ministerio de Ciencia e Innovación (SAF2011-22463). 2012-2014.
Desarrollo de nuevos procedimientos diagnósticos y terapéuticos basados en la tecnología de GPBP. MICINN-INNPACTO (IPT-2011-1527-010000). Entidades participantes: Fibrostatin S.L. (Valencia), Universidad de Valencia, Universidad de Cantabria (UC). Sept-2011-Dec-2014.
Relevant publications (last 10 years)
1. J. Chimal-Monroy, J. Rodriguez-Leon, J.A. Montero, Y. Gañan, D. Macias, R. Merino and J.M. Hurle. Analysis of the molecular cascade responsible for mesodermal limb chondrogenesis: Sox genes and BMP signaling. Dev. Biol. 2003, 257:292-301.
2. M. López-Hoyos, R. Marquina, E. Tamayo, J. González-Rojas, S. Izui, R. Merino* and J. Merino*. Defects in the regulation of B cell apoptosis are required for the production of citrullinated peptide autoantibodies in mice. Arthritis Rheum. 2003, 48:2353-2361.
*Senior Authorship
3. R. Merino and J.M. Hurlé. The molecular basis of retinoid action in tumours. Trends Mol. Med. 2003, 9:509-511.
4. A. Kuroki, T. Moll, M. López-Hoyos, L. Fossati-Jimack, N. Ibnou-Zekri, S. Kikuchi, J. Merino, R. Merino and S. Izui. Enforced BCL-2 expression in B lymphocytes induces rheumatoid factor and anti-DNA production, but the Yaa mutation promotes only anti-DNA production. Eur. J. Immunol. 2004, 34:1077-1084.
5. R. Marquina, M.A. Díez, M. López-Hoyos, L. Buelta, A. Kuroki, S. Kikuchi, J. Villegas, M. Pihlgren, C.A. Siegrist, M. Arias, S. Izui, J. Merino and R. Merino. Inhibition of B cell death causes the development of an IgA nephropathy in (NZW x C57BL/6)F1-bcl-2 transgenic mice. J. Immunol. 2004, 172:7177-7185.
6. Vossenaar ER, MAM van Boekel, WJ van Venrooij, M López-Hoyos, J Merino, R Merino and LAB Joosten. Absence of citrulline-specific antibodies in animal models of arthritis. Arthritis Rheum. 2004, 50:2370-2372.
7. V. Zuzarte-Luis, J.A. Montero-Simon, J. Rodríguez-León, R. Merino, J.C. Rodriguez-Rey and J.M. Hurle. A new role for BMP5 during limb development acting through the synergic activation of Smad and MAPK pathways. Dev. Biol. 2004, 272:39-52.
8. P. Mora, I. Masip, N. Cortés, R. Marquina, R. Merino, J. Merino, T. Carbonell, I. Mingarro, A. Messeguer and E. Pérez-Payá. Identification from a positional scanning peptoid library of in vivo active compounds that neutralize bacterial endotoxins. J. Med. Chem. 2005, 48:1265-1268.
9. E. Tamayo, R. Merino, J. González-Rojas, R. Marquina, I. Santiuste, J.A. Amado, R. Rappuoli, G. Del Giudice and J. Merino. The Escherichia coli heat-labile enterotoxin induces apoptosis of immature lymphocytes in vivo via a glucocorticoid-dependent pathway. Eur. J. Immunol. 2005, 35:3505-3515.
10. D. San Segundo, J.C. Ruiz, G. Fernández-Fresnedo, M. Izquierdo, C. Gómez-Alamillo, R. Merino, M.J. Benito, E. Cacho, E. Rodrigo, R. Palomar, M. López-Hoyos, M. Arias. Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4+CD25+FOXP3+ regulatory T cells in renal transplant recipients. Transplantation 2006, 82:550-557.
11. J. González, E. Tamayo, I. Santiuste, R. Marquina, L. Buelta, M.A. González-Gay, S. Izui, M. López-Hoyos, J. Merino and R. Merino. CD4+CD25+ T cell-dependent inhibition of autoimmunity in transgenic mice overexpressing human Bcl-2 in T lymphocytes. J. Immunol. 2007, 178: 2778–2786.
12. F. Revert, R. Merino, C. Monteagudo, J. Macias, A. Peydró, J. Alcácer, P. Muniesa, R. Marquina, M. Blanco, M. Iglesias, F. Revert-Ros, J. Merino and J. Saus. Increased GPBP expression induces type IV collagen disorganization and deposit of IgA in glomemular basement membrane. Am. J. Pathol. 2007, 171:1419-1430.
13. E. Tamayo, J. Postigo, G. del Giudice, R. Rappuoli, A. Benito, H. Yagita, R. Merino* and J. Merino*. Involvement of the intrinsic and extrinsic cell death pathways in the induction of apoptosis of mature lymphocytes by the Escherichia coli heat-labile enterotoxin. Eur. J. Immunol. 2009, 39: 439-446.
*Senior Authorship
14. A.V. Villar, M. Llano, M. Cobo, V. Expósito, R. Merino, R. Martín-Durán, M.A. Hurlé, and J.F. Nistal. Gender differences of echocardiographic and gene expression patterns in human pressure overload left ventricular hypertrophy. J. Mol. Cell. Card. 2009, 46: 526-535.
15. MªA. Ramos-Barrón, C. Gómez-Alamillo, I. Santiuste, C. Agüeros, L. San Cosme, A. Benito, T. Gimenez, J. Merino, R Merino and M Arias. Leflunomide derivative FK778 inhibits production of antibodies in an experimental nodel of alloreactive T-B cell interaction. Exp. Clin. Trasplant. 2009, 4: 218-224.
16. E. Tamayo, J. Postigo, J. González, M. Fernández-Rey, M. Iglesias, I. Santiuste, C. Riccardi, R. Rappuoli, G. del Giudice, R. Merino* and J. Merino*. The Glucocorticoid-Induced TNFR-Related protein (GITR) contributes to the systemic adjuvanticity of the Escherichia coli heat-labile enterotoxin. Eur. J. Immunol. 2010, 40: 754-763.
*Senior Authorship
17. M. Tramullas, A. Lantero, A. Díaz, N. Morchón, D. Merino, A. Villar, D. Buscher, R. Merino, J.M. Hurlé, J.C. Izpisúa-Belmonte, M.A. Hurlé. BMP and Activin membrane-bound inhibitor (BAMBI) reveals the involvement of the TGF-β family in pain modulation. J. Neurosci. 2010, 30: 1502-1511.
18. I. Santiuste, L. Buelta, M. Iglesias, F. Genre, F. Mazorra, S. Izui, J. Merino and R. Merino. B-cell overexpression of Bcl-2 cooperates with p21 deficiency for the induction of autoimmunity and lymphomas. J. Autoimmun. 2010, 35: 316-324.
19. J. Postigo., F. Genre, M. Iglesias, M. Fernández-Rey, L. Buelta, J.C. Rodríguez-Rey, J. Merino and R. Merino. Exacerbation of collagen type II-induced arthritis in ApoE deficient mice in association with the expansion of Th1 and Th17 cells. Arthritis Rheum. 2011, 63: 971-980. DOI: 10.1002/art.30220.
20. J. Postigo, M. Iglesias, A. Rosal-Vela, S. García-Rodríguez, M. Zubiaur, J. Sancho, R. Merino* and J. Merino*. Mice deficient in CD38 develop an attenuated form of collagen type II-induced arthritis. PLoS ONE 2012, 7: e33534. DOI:10.1371/journal.pone.0033534.
*Senior Authorship
21. M. Iglesias, J. Postigo, I. Santiuste, J. González, L. Buelta, E. Tamayo, J. Merino and R. Merino. p27kip1 inhibits systemic autoimmunity through the control of regulatory T cell activity and differentiation. Arthritis Rheum. 2013, 65: 343-354. DOI: 10.1002/art.37778.
Contact:
Dr. Ramón Merino
Departamento de Biología Molecular
IBBTEC-Universidad de Cantabria
Phone: (+34) 942 201956
Fax:(+34) 942 201945
merinor@unican.es
