GENETIC FACTORS FOR PROGRESSION OF HIV ASSOCIATED NEPHROPATHY

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Similar to many systemic disorders, HIV-1 infection causes end-stage renal disease (ESRD) in defined population subgroups, primarily African Americans, thereby suggesting that genetic risk factors have a critical role in the development of renal failure. The aim of this project is to map the quantitative trait loci (QTL's) relevant to the development of ESRD by focusing on a murine model of HIV-1 associated nephropathy (HIVAN). To achieve this goal, Core B will provide a carefully phenotyped B2 cross between the HIV-1 transgenic mouse line (Tg26) and M. cataneus (MCAST) strains. This project will perform mapping of QTL's. This effort will constitute a critical step toward identification of underlying trait loci contributing to renal failure. The function of this project will address the following aims: 1. Identification of a screening set of 160 simple sequence length polymorphisms spaced at approximately 10 cM intervals that are informative in the Tg26 x MCAST cross. 2. Genotypic analysis of animals in the B2 cohort followed by analysis of linkage comparing the segregation of each trait to marker loci spanning the mouse genome. 3. Genetic characterization of congenic strains trapping the QTLs identified in aim 2. 4. Fine mapping of the QTL by meiotic mapping of the congenic strains followed by identification of the gene(s) response for the development of renal failure by candidate gene analysis and positional cloning. It is believed that placing performance of much of the molecular genetics of the program project in a single project with established expertise is logical, since it maximizes use of personnel and equipment employed in repetitive tasks such as marker development, genotyping and analysis of linkage.