Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are chronic inflammatory autoimmune diseases with a female predominance (RA 3:1, SLE 9:1). These sex ratios constitute a clinical fact, but the reason is not yet fully understood. It is necessary to investigate the underlying mechanisms to understand the biology of these diseases and to open new therapeutic options. Epidemiological studies and experimental evidences suggest that female sex hormones exert an important role in the pathogenesis of RA and SLE since pregnancy and menopausal status are recognized as factors influencing the course of the disease. However the role of estrogens in chronic- inflammatory diseases is still controversial discussed. Beside sex hormones unbalanced inactivation of the maternal and paternal X chromosome in women may influence the occurrence of the autoimmune diseases. Also epigenetic mechanisms, such as alteration in methylation patterns of the X-chromosome, could contribute to gender differences in the diseases. In a total genomic microarray analysis we want to identify gender specific regulated genes. The mechanisms of this differential gene expression will be analyzed in cell culture experiments and in animal models.
The current treatment for RA and SLE includes glucocorticoids, immunosuppressive agents, monoclonal antibodies and antimalarial drugs. Despite the recent advances in RA and SLE therapy, a number of patients fail to respond, respond inadequate to these drugs or they have severe adverse effects. Therefore, there is a need to identify new therapeutics and new drug targets to improve the current treatment regimes for RA and SLE.
In cooperation with PD Dr. Erkel (TU Kaiserslautern) and PD Dr. Menke (UM Mainz) we analyze the effects of new anti-inflammatory natural compounds in RA and SLE animal models
Chronic inflammatory diseases are characterized by dysregulated expression of pro-inflammatory genes leading to an abnormal accumulation of immune cells in the organs affected. The expression of pro-inflammatory genes is regulated on transcriptional and post- transcriptional levels. The most important mechanism in the post-transcriptional regulation of gene expression is modulation of mRNA stability. The mRNA stability is determined by AU-rich sequences, which serve as binding sites for different RNA binding proteins. The importance of RNA binding proteins for the development of a chronic inflammation has been demonstrated in several animal models. But almost nothing is known about the regulation of these proteins in RA or SLE or their function in immune cells. Therefore, we want to investigate the role of the different RNA binding proteins in the pathogenesis of RA and SLE.
microRNAs (miRNAs) are a class of small non coding RNAs that control gene expression by regulating mRNA stability or translation. Some reports describe that the expression of some miRNAs is upregulated in RA or SLE. The role of these miRNAs in disease pathogenesis remains to be elucidated as well as identification of their target genes. The focus of our studies is the identification of miRNAs and their target genes in RA and SLE
During the last years it has been established that systemic inflammation enhances the development of atherosclerosis. This is illustrated by the increased risk of RA or SLE patients to develop cardiovascular disorders. In RA patients, for example, cardiovascular diseases are the main cause of death. The increased expression of pro-inflammatory mediators in these patients seems to be crucially involved in the pathogenesis of cardiovascular disorders. Therefore, chronic systemic inflammation can be considered as an independent risk factor for the development of atherosclerosis and related cardiovascular diseases. We want to identify underlying molecular mechanisms using a total genomic microarray approach.
As atherosclerosis is considered as an inflammatory disease treatment with anti-phlogistic drugs could serve as a new therapeutic concept. Therefore, we want to characterize the anti-atherosclerotic/thrombotic effects of new anti-inflammatory natural compounds in murine models.
We use a broad range of molecular biology methods as quantitative real-time-RT-PCR, PCR, cloning, microarray analysis, western blot, gene reporter assays, cell culture, transfection experiments and animal studies.