Systemic lupus erythematosus (SLE), a multi-system disorder with significant morbidity and mortality affects predominantly females in their reproductive years. Genetic and environmental factors play significant roles in its pathogenesis. Despite significant progress, immune mediated glomerulonephritis (GN) remains a major cause of end stage renal failure. The PI's laboratory has been focused on the genetic aspect of lupus GN by studying the murine model NZM2328. This competitive renewal application is to continue the PI's research program to identify lupus susceptibility genes, Cgnz1 and Adnz2, on chromosome 1 that confer the production of antinuclear and related autoantibodies (Ab) and end organ resistance to the development of chronic glomerulonephritis (cGN) respectively in NZM2328, a much studied model for human proliferative lupus nephritis. During the currrent grant period, two informative congenic lines, 290-2 and 507-2 were generated and characterized. This analysis led to the conclusion that this region has been narrowed to a 1.34Mb area that is very much amendable to further analysis. The separation of autoimmunity and end organ damage is unique and the PI's laboratory remains the major site to focus on the genes which contribute to end organ resistance to damage. A team of investigators with complementary skills have been assembled to utilize up-to- date techniques in molecular and cell biology and animal genetics to resolve this technically demanding research project. To achieve the long term objective of this program, four specific aims are proposed:
Specific Aim 1 : To generate and to characterize the NZM.C57Lc1 recombinant congenic strain Lc1(1.34Mb) that contains the 1.34Mb of interest by intercross breeding (NZM2328X507-2)F1 X (NZM2328X507-2)F1;
Specific Aim 2 : To identify a set of contiguous overlapping genomic clones (contigs) from the NZM2328 BAC library, which cover the 1.34 Mb region of interest and to sequence these contigs to define polymorphisms in this region by comparing the sequences with those of 129 and B6/C57L available in the database. The polymorphisms may also identify potential candidate genes for Cgnz1 and Adaz2;
Specific Aim 3 : To determine the transcriptional profiles of the 45 genes within this region in intrinsic kidney cells and in immune cells including T and B cells, dendritic cells, monocytes and macrophages and NK cells to identify candidate genes responsible for kidney resistance to damage and for those for enhanced autoimmune response and Specific Aim 4: To validate susceptibility by gene knockin technology or allele transgenesis. The results will provide conclusive evidence that genes controlling end organ damage play an important role in lupus nephritis and that they interact with genes that enhance autoimmunity resulting in various clinical presentations. On the basic level, the results may alter our thinking on the pathogenesis of autoimmune disorders. In addition, these results have significant clinical implication in that genetic factors may allow us to tailor individual therapeutic regimens for lupus nephritis to maximize therapeutic goals and to minimize toxic side effects.

Public Health Relevance

Systemic lupus erythematosus is a disease affecting many organs. It causes a significant amount of suffering and early death. It affects predominantly females at their reproductive ages. Genetic factors play a significant role. Despite significant progress in research, renal disease remains a major cause of end stage renal failure that requires either chronic dialysis or renal transplantation. This proposal is to seek funding to continue a research program to identify genetic factors that affect autoimmunity and render the kidney resistant to damage by autoantibodies and/or autoreactive lymphocytes. The research program is taking advantage of the unique mouse models established in the investigators'laboratory. The results of the research program can be readily translated to patient care in that individual patients can be treated with individual regimens for their renal disease and to maintain them in remission. This will reduce the morbidity and mortality significantly so that patients can remain active and productive. Thus the research program should have significant impact on public health.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Mancini, Marie
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University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
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