Experimental Autoantibody Induced Glomerulo Nephritis (AIGN) elicited by the adoptive transfer of anti-GBM (or anti-glomerular) Abs is a good model of human anti- GBM/Goodpasture's disease. In addition, the downstream pathogenic mechanisms mediating disease in AIGN overlap with the pathogenic cascades leading to lupus nephritis (LN). Hence, genes and molecular mechanisms uncovered using the AIGN model may also play key roles in spontaneous LN. Indeed, we already have evidence that some of the loci/genes implicated in LN do also facilitate AIGN. Given this potential significance, we adopted a comprehensive strategy to search for genes and molecular mechanisms that influence AIGN in mice. Out of >20 inbred strains we surveyed, the BUB, C58, NZW, DBA/1 and 129/sv strains turned out to be the most sensitive to AIGN. Over the previous cycle of funding, we have studied 3 disease- sensitive strains - DBA/1, 129/sv and NZW, and have identified the strongest genetic loci for disease in each of these 3 strains. In addition, our more recent microarray studies (of the renal cortex) comparing AIGN- sensitive and the AIGN-resistant strains have identified tissue kallikreins and PDGFRb as potential candidates within these disease loci. In the next cycle of funding, we propose to examine these implicated disease loci using "congenic dissection" and candidate gene analysis. Collectively, these studies are likely to shed novel light on the genetic and molecular origins of antibody-mediated nephritis.

Public Health Relevance

Currently, we do not have a clear understanding of the genetic and molecular origins of antibody mediated renal disease, which lies at the heart of many illnesses, including lupus. By surveying more than 20 inbred mouse strains we have identified 3 strains that might hold clues to this puzzle. By studying the genomes of these 3 strains, we have identified 4 genetic loci that could shed light on this important question, and this forms the basis of this renewal application. Understanding which molecules dictate renal disease can potentially lead to novel therapeutic options in nephritis due to lupus, diabetes and hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050812-09
Application #
8274359
Study Section
Special Emphasis Panel (ZRG1-HAI-G (09))
Program Officer
Mancini, Marie
Project Start
2003-09-30
Project End
2013-07-31
Budget Start
2012-06-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$323,979
Indirect Cost
$117,623
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Li, Yajuan; Li, Wei; Liu, Chu et al. (2014) Delivering Oxidation Resistance-1 (OXR1) to Mouse Kidney by Genetic Modified Mesenchymal Stem Cells Exhibited Enhanced Protection against Nephrotoxic Serum Induced Renal Injury and Lupus Nephritis. J Stem Cell Res Ther 4:
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Wu, Tianfu; Ye, Yujin; Min, So-Youn et al. (2014) Prevention of murine lupus nephritis by targeting multiple signaling axes and oxidative stress using a synthetic triterpenoid. Arthritis Rheumatol 66:3129-39
Shao, Xinli; Yang, Ru; Yan, Mei et al. (2013) Inducible expression of kallikrein in renal tubular cells protects mice against spontaneous lupus nephritis. Arthritis Rheum 65:780-91
Li, Yajuan; Raman, Indu; Du, Yong et al. (2013) Kallikrein transduced mesenchymal stem cells protect against anti-GBM disease and lupus nephritis by ameliorating inflammation and oxidative stress. PLoS One 8:e67790
Min, S-Y; Yan, M; Du, Y et al. (2013) Intra-articular nuclear factor-κB blockade ameliorates collagen-induced arthritis in mice by eliciting regulatory T cells and macrophages. Clin Exp Immunol 172:217-27
Li, Yajuan; Fang, Xiangdong; Li, Quan-Zhen (2013) Biomarker profiling for lupus nephritis. Genomics Proteomics Bioinformatics 11:158-65
Cuda, Carla M; Agrawal, Hemant; Misharin, Alexander V et al. (2012) Requirement of myeloid cell-specific Fas expression for prevention of systemic autoimmunity in mice. Arthritis Rheum 64:808-20
Singh, Sandeep; Wu, Tianfu; Xie, Chun et al. (2012) Urine VCAM-1 as a marker of renal pathology activity index in lupus nephritis. Arthritis Res Ther 14:R164

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