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9. Center of Rheumatology and WHO Collaborating Center, Zurich:
We are interested in the transcriptional and post-transcriptional mechanisms of gene regulation in Rheumatoid Arthritis (RA) and Systemic Sclerosis (SSc). So called epigenetic changes include any process that alters gene activity without changing the DNA sequence. Many types of epigenetic transcriptional processes such as methylation, acetylation, phosphorylation, ubiquitination, sumoylation, and posttranscriptional processes such as micro RNAs and small interfering RNAs are known, that either modulate the DNA or the chromatin structure. We are interested in acetylation processes. Acetylation is associated with increased gene transcription since the removal of positive charges of the histone tails enables the recruitment of transcription factors to the DNA. Deacetylation, the reverse process, is associated with gene repression. Histone deacetylases (HDACs) are divided into three classes: class I HDACs (HDACs 1, 2, 3, and 8) are localize to the nucleus; class II HDACs (HDACs 4, 5, 6, 7, 9, and 10) are found in both the nucleus and cytoplasm; and class III HDACs form a structurally distinct class of NAD-dependent enzymes that are found in the cytoplasm. In our lab, we are particularly interested in understanding how the activity of histone-acetylases (HAT) and histone-deacetylases (HDAC) contributes to the inflammatory diseases and how we can modulate these processes by knock down approaches of RNAs using siRNA for single HDACs or HDAC inhibitors such as Trichostin A. We plan to define tissue specific expression pattern of these enzymes in synovial tissues from patients with RA and OA and skin tissues from patients with SSc. In addition we will investigate whether inflammatory cytokines involved in the pathogenesis of these diseases influence the expression pattern of HATs and HDACs.
a. description of the group
The Center for Experimental Rheumatology is part of the Zurich Center for Integrative Human Physiology (ZIHP) and serves as an institution for molecular research in the field of rheumatoid arthritis (RA) and related autoimmune diseases. Recognized as being a leader in this field, the laboratory was for the second consecutive term, selected to be the World Health Organization Collaborating Center for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases from 2003 to 2007 (www.who.int/en/). The laboratory continues its pursuit of discovering, investigating and understanding key molecular and cellular events in RA, osteoarthritis, ankylosing spondylitis, progressive systemic sclerosis and prosthesis loosening.
The center was awarded from the Societas Rheumatologica Europeae to a EULAR Center of Excellence in Rheumatology 2005-2010.
The center is part of the AUTOCURE project sponsored with 11 Mio. Euros by the EC within the FP6 program from 2006-2011. Involved in the project are 26 different partners of which 6 are industrial partners and 20 are from all over Europe.
Read more: www.autocure.org.
The center is also part of the EC supported EURO-RA Marie Curie Actions Research Training Networks (RTNs).
When investigating such complex diseases as rheumatoid arthritis it is critical to combine the knowledge and ideas of basic research with those of the clinical elements of the disease. As such, the Center for Experimental Rheumatology fosters a multidisciplinary environment through collaborations with several major medical institutions where practicing Rheumatologists, Immunologists, and Orthopedic Surgeons are able to interact with research scientists to form coordinated research efforts integrating basic research and clinical investigation.
To be on edge of new strategies for the treatment of rheumatic diseases the Center developed a new program entitled " Clinical and Molecular Studies on Novel Drug Therapies".
New research investigations currently focus on molecular mechanisms of cartilage and bone destruction, with particular emphasis on the activation of signaling pathways in synovial fibroblasts that lead to the destructive behavior of these cells. Gene transfer experiments in murine models of RA are designed to detect and/or verify novel therapeutic targets. The aim of these experiments is to inhibit the aggressive process of destruction by activated synovial fibroblasts. This is achieved by selectively interrupting already identified signals of fibroblast activation, while not interfering with other, essential, physiological processes.
A new and exciting avenue of research is the profiling of synovial fibroblast gene expression in a hypoxic environment with a focus on genes involved in cartilage and bone degradation.
b. scientist in charge
Steffen Gay, MD
Professor Steffen Gay graduated from Medical School at the University in Leipzig. Holding office from 1976-1996 at the Department of Medicine at the University of Alabama in Birmingham AL, he served there as Professor of Medicine from 1984-1996. At present he is Director of the WHO Collaborating Centre for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases and Professor of Experimental Rheumatology at the University Hospital of Zurich, Switzerland. Steffen Gay served as Chairman of the International Advisory Committee at the American College of Rheumatology and held the charge of Spinoza Professor at the University of Amsterdam in 2002. He is an Honorary Member of the American Association of Physicians and of The Alpha Omega Honor Medical Society. His research center was awarded an EULAR "Centre of Excellence in Rheumatology" from 2005-2010. He has published over 300 peer-reviewed scientific papers and is listed by the Institute for Scientific Information as among the most cited authors in clinical medicine.
c. other supporting scientists
Renate E. Gay, MD, Professor, renate.gay@usz.ch
Michel Neidhart, PhD, PD, Oberassistent, michel.neidhart@usz.ch
Haiko Sprott, MD, PD, Leitender Arzt, haiko.sprott@usz.ch
Diego Kyburz, MD, PD, Leitender Arzt, diego.kyburz@usz.ch
Adrian Ciurea, MD, Oberarzt, adrian.ciurea@usz.ch
Oliver Distler, MD, PD, oliver.distler@usz.ch
d. fellows
Jörg Goldhahn, MD, Postdoc, joerg.goldhahn@kws.ch
Falk Moritz, MD, Postdoc, falk.moritz@usz.ch
Lars C. Huber, MD, Postdoc, lars.huber@usz.ch
Caroline Ospelt, MD, Postdoc, caroline.ospelt@usz.ch
Joanna Stanczyk, MD, Postdoc, joanna.stanczyk@usz.ch
Hossein Hemmatazad, MD, Postdoc, hossein.hemmatazad@usz.ch
Olga Sanchez Pernaute, MD, Postdoc, olga.sanchez@usz.ch
Astrid Jüngel, PhD, Postdoc, astrid.juengel@usz.ch
Fabia Brentano, PhD-student, fabia.brentano@usz.ch
Peter Künzler, MSc, Research Associate, peter.kuenzler@usz.ch
e. link
http://www.rheumatologie.usz.ch/german/LehreUndForschung/Forschung/ExperimentalRheumatology/default.htm
f. projects selected for the Marie Curie founded training
Apoptosis
Summary
Rheumatoid arthritis (RA) is a chronic disease of unknown etiology that results in a progressive destruction of cartilage and bone in affected joints. During the course of RA, the synovial tissue becomes remarkably hyperplastic and invades cartilage and bone. The mechanisms resulting in the hyperplasia of RA synovium have not jet been fully elucidated. Possible mechanisms are resistance against cell death, increase proliferation or even both.
Our group showed that the small ubiqutin-like modifier (SUMO)-1 is expressed in the synovium of patients with RA but not OA. The expression of SUMO-1 in RA synovial fibroblasts (RASF) and especially in the synovium at sites of cartilage invasion suggests a role of SUMO-1 in apoptotic pathways in RA.
In BJAB-cells it is shown that SUMO-1 is associated with alterations in apoptosis by binding the death domain of Fas (FADD). Furthermore, SUMO-1 is involved in the formation of promyeloic leukaemia protein nucler bodies (PML-NBs), these are macromolecular domains in all mammalian cells which can be functionally linked to apoptosis. These PML bodies accumulate and interact with the "death-domain associated protein" DAXX in the nucleus. It is known that SUMO-1 binds and modifies DAXX. During apoptosis DAXX specifically binds to the death domain of the transmembrane death receptor FAS.
In our lab, we are particular interested whether SUMO-1 is involved in the resistance of RASF against Fas-induced apoptosis. We will analyze the expression levels of the nuclear protease SENP-1 in RASF and OASF that hydrolyzes SUMO-1. Furthermore, we are interested in modulation of apoptosis-inhibitory effects in RASF by over expression of the SENP-1 protease. Interactions of SUMO-1, PML-NBs and DAXX should give us important insights into the signaling pathways after Fas-induced apoptosis in RASF.
Publications
Jüngel A, Baresova V, Ospelt C, Simmen BR, Michel BA, Gay RE, Gay S, Seemayer CA, Neidhart M. Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apoptosis. Ann Rheum Dis 65:910-2, 2006
Project Leadership and Contacts
Prof. Dr. Steffen Gay (Project Leader) steffen.gay@usz.ch
Dr. Astrid Jüngel, PhD astrid.juengel@usz.ch
Funding Source(s)
SNF (Program NFP)
EU Grant Marie Curie
Duration of Project
Jan 2005 to Dec 2007
Epigentetics Acetylation-Deacetylation
Summary
We are interested in the transcriptional and post-transcriptional mechanisms of gene regulation in Rheumatoid Arthritis (RA) and Systemic Sclerosis (SSc). So called epigenetic changes include any process that alters gene activity without changing the DNA sequence. Many types of epigenetic transcriptional processes such as methylation, acetylation, phosphorylation, ubiquitination, sumoylation, and posttranscriptional processes such as micro RNAs and small interfering RNAs are known, that either modulate the DNA or the chromatin structure. We are interested in acetylation processes. Acetylation is associated with increased gene transcription since the removal of positive charges of the histone tails enables the recruitment of transcription factors to the DNA. Deacetylation, the reverse process, is associated with gene repression. Histone deacetylases (HDACs) are divided into three classes: class I HDACs (HDACs 1, 2, 3, and 8) are localize to the nucleus; class II HDACs (HDACs 4, 5, 6, 7, 9, and 10) are found in both the nucleus and cytoplasm; and class III HDACs form a structurally distinct class of NAD-dependent enzymes that are found in the cytoplasm. In our lab, we are particularly interested in understanding how the activity of histone-acetylases (HAT) and histone-deacetylases (HDAC) contributes to the inflammatory diseases and how we can modulate these processes by knock down approaches of RNAs using siRNA for single HDACs or HDAC inhibitors such as Trichostin A. We plan to define tissue specific expression pattern of these enzymes in synovial tissues from patients with RA and OA and skin tissues from patients with SSc. In addition we will investigate whether inflammatory cytokines involved in the pathogenesis of these diseases influence the expression pattern of HATs and HDACs.
Publications
Jüngel A, Baresova V, Ospelt C, Simmen BR, Michel BA, Gay RE, Gay S, Seemayer CA, Neidhart M. Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apoptosis. Ann Rheum Dis 65:910-2, 2006.
Project Leadership and Contacts
Prof. Dr. Steffen Gay (Project Leader) steffen.gay@usz.ch
Dr. Astrid Jüngel, PhD astrid.juengel@usz.ch
Funding Source(s)
EU Grant AUTOCURE 2006-2011
EU Grant Marie Curie
Duration of Project
Mar 2006 to Dec 2008
Other related projects of this Center can be found at:
http://www.research-projects.unizh.ch/a463.htm
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