? Lupus prone mouse model MRL/lpr develop an early onset autoimmune disease displaying a ? pathogenesis similar to that observed in human SLE with most mice dying of renal failure. Normal mice ? develop an autoimmune kidney disease similar to that observed in lupus prone mouse models in which the Ets transcription factor Fli1 has been over-expressed. Subsequently, FN1 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 PBMCs 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 suggest strongly that Fli1 plays an important role in the pathogenesis of lupus. Furthermore, our preliminary studies indicate that Fli1 is over-expressed specifically in CD8+ T lymphocytes in MRL/lpr mice and that a polymorphism located in the promoter region of Fli1 affects its expression in a T cell line. We hypothesize that elevated levels of Fli1 in CD8+ T lymphocytes alter their proliferation, survival and/or function, specifically suppressor function, through the dysregulation of Fli1 target gene expression. The analysis of genes and gene products that regulate the immune system is central to understanding autoimmunity and research shows that FN1 clearly has effects on the immune system. Therefore, understanding the effects of over-expressing Fli1 and its transcriptional regulation in normal lymphocytes is necessary before we can begin to analyze and understand its dysregulation and role in lupus disease. Our long-term goal is to design methods to down-regulate Fli1 and identify other factors in the FN1 regulatory pathway as potential therapeutic targets in the treatment for human lupus. Currently, little is known regarding what role Fli1 plays in lymphocyte function or how FH1 gene expression is regulated in lymphocytes. To test our hypothesis and to lay the groundwork for our long-term goal, we propose to study the function and regulation of Fli1 in CD8+ T lymphocytes. Specifically, we propose the following: 1) Determine the molecular and phenotypic effects of over-expressing Fli1 in CD8+ T lymphocytes. To isolate the effects due solely to FN1 over-expression, we will analyze the molecular and phenotypic effects in CD8+ T lymphocytes isolated from control mice in which we over-express Fli1. 2) Identify mechanisms involved in ? the transcriptional regulation of Fli1 gene expression in CD8+ T lymphocytes. The major objective of these studies is to identify the trans-acting factors involved in the regulation of Fli1 expression in splenic CD8+ T lymphocytes. Results from these studies will be the foundation for future studies aimed at developing therapies for treating lupus patients. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR053376-02
Application #
7393257
Study Section
Special Emphasis Panel (ZAR1-EHB-M (O1))
Program Officer
Mancini, Marie
Project Start
2007-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$71,540
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Sundararaj, Kamala P; Thiyagarajan, Thirumagal; Molano, Ivan et al. (2015) FLI1 Levels Impact CXCR3 Expression and Renal Infiltration of T Cells and Renal Glycosphingolipid Metabolism in the MRL/lpr Lupus Mouse Strain. J Immunol 195:5551-60
Schnabolk, Gloriane; Coughlin, Beth; Joseph, Kusumam et al. (2015) Local production of the alternative pathway component factor B is sufficient to promote laser-induced choroidal neovascularization. Invest Ophthalmol Vis Sci 56:1850-63
Hoffecker, Brett M; Raffield, Laura M; Kamen, Diane L et al. (2013) Systemic lupus erythematosus and vitamin D deficiency are associated with shorter telomere length among African Americans: a case-control study. PLoS One 8:e63725
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
Morris, Erin E; Amria, May Y; Kistner-Griffin, Emily et al. (2010) A GA microsatellite in the Fli1 promoter modulates gene expression and is associated with systemic lupus erythematosus patients without nephritis. Arthritis Res Ther 12:R212