Identifying the earliest events in HIV-1 associated nephropathy via genome-wide

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DESCRIPTION (provided by applicant): The goals of this project are to use a validated mouse model to dissect molecular pathways mediating he development of HIV-1 associated nephropathy (HIVAN). HIVAN is a major complication of HIV-1 infection with distinct pathologic features. This disorder is caused by HIV-1 induced dedifferentiation of glomerular podocytes, the terminally differentiated epithelial cells that maintain the structure of the kidney filtration barrier. Genetic susceptibility to HIVAN has complex determination, with significant contribution from genetic variation in the nonmuscle myosin heavy chain 9 (MYH9), a podocyte expressed gene. HIV-1 transgenic mice on the FVB/NJ genetic background recapitulate all the clinical and pathologic hallmarks of HIVAN. Using mapping cohorts between mice with contrasting susceptibility to HIVAN, we have identified three nephropathy susceptibility loci that map to chromosomes 3, 13, 4 respectively (named HIVAN1- 3) and have confirmed mapping data by examination of congenic mice that capture these intervals. By combining linkage analysis with gene expression profiling (eQTL mapping) in F2 segregants, we have also demonstrated that the murine HIVAN susceptibility loci encode transregulators of podocyte gene expression and belong to the same pathway as known human nephropathy genes (Myh9, Podocin, Nephrin, Cd2ap). The introduction of HIV-1 results in significant perturbations of the relationship between genotype and expression of specific sets of podocyte genes, indicating that HIV-1 interferes with transregulation. These considerations indicate that careful dissection of clinical and molecular phenotypes associated with each HIVAN locus and identifications of genes that demonstrate the greatest perturbation in transregulation upon HIV-1 exposure can elucidate the earliest events in the initiation of nephropathy and delineate dysregulated molecular networks mediating disease pathogenesis. To achieve these aims, we will first perform phenotypic characterization of HIVAN congenic mice to identify the contribution of each locus to initiation and progression of disease. Next we will perform analysis of glomerular transcriptome in HIV-1 transgenic congenic mice and wiltype counterparts to infer the glomerular interactome in HIVAN and discover genes that demonstrate aberrant patterns of transregulations. Finally, these genes will be validated by eQTL mapping in HIVAN segregants, by functional studies in human podocytes and ultimately, by generation of transgenic lines that will confirm findings. Identification of molecular mediators of HIVAN is expected to provide significant insight into the pathogenesis of disease and provide novel targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: HIV-1 associated nephropathy is a major complication of HV-1 infection and a significant cause of kidney failure worldwide. Identification of molecular mediators of HIVAN is expected to provide significant insight into the pathogenesis of disease and provide novel targets for therapeutic intervention.