Systemic lupus erythematosus (SLE) is an increasingly prevalent systemic autoimmune disease affecting the joints, muscles, heart, lungs, blood, kidneys, skin and the central nervous system. Renal disease (lupus nephritis) is a common manifestation affecting up to two-thirds of lupus patients and is a major cause of morbidity and mortality. The lupus prone mouse models MRL/lpr and NZM 2410 develop an early onset autoimmune disease displaying a pathogenesis similar to that observed in human SLE with most mice dying of renal failure. Interestingly, when the transcription factor Fli1 is over-expressed in normal, healthy mice, the mice develop an autoimmune kidney disease similar to that observed in lupus prone mouse models. Subsequently, Fli1 was shown to be over-expressed in the splenic T cells of the lupus prone NZB/NZW f1 mouse strain, the spleen of lupus prone MRL/lpr mice, and lymphocytes of SLE patients. Furthermore, genetically lowering the levels of Fli1 in MRL/lpr mice by 50% significantly decreased autoantibody production, improved kidney disease and prolonged survival. Together, these studies strongly suggest that dysregulation and resulting over-expression of Fli1 plays a role in the pathogenesis of lupus. We hypothesize that the over-expression of Fli1 in lupus is a key event in the pathogenesis of lupus resulting from dysregulation of Fli1 gene transcription. To address our hypothesis we have proposed three aims.
In specific aim 1 we propose to determine specifically which lymphocyte subsets in lupus prone mice over-express Fli1 compared to healthy, disease free controls. In addition we will analyze the rate of transcription and the message stability of Fli1 in lymphocyte subsets that over-express Fli1 in lupus prone mice compared to control mice.
In specific aim 2 we propose to determine what cis-regulatory elements within the Fli1 promoter region are necessary for expression in control lymphocytes and what elements are involved in the over-expression in lymphocytes from lupus prone mice.
For specific aim 3, we propose to identify transcription factors that bind to cis-regulatory elements in the Fli1 promoter in control lymphocytes and """"""""disease"""""""" lymphocytes. The studies proposed in this application will further the understanding of the role of Fli1 in lupus and the molecular mechanisms involved in disease expression.
| Svenson, J L; Chike-Harris, K; Amria, M Y et al. (2010) The mouse and human Fli1 genes are similarly regulated by Ets factors in T cells. Genes Immun 11:161-72 |
| Nowling, Tamara K; Fulton, Jennifer Dziadyk; Chike-Harris, Katherine et al. (2008) Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes. Mol Immunol 45:1-12 |
