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.
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.
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