The aims of this project are to apply genomic approaches to delineate mechanisms underlying the development of HIV associated nephropathy (HIVAN), one of the most common causes of renal failure. Using HIV-1 transgenic mice (TgFVB), we have already identified one QTL mediating severity of renal disease on mouse chromosome 3. We propose to identify this QTL and other QTL's controlling the development of renal disease through analysis of congenic strains and additional mapping cohorts, using a combination meiotic mapping, haplotype resolution, gene expression studies and sequence data mining.
The specific aims of this project are: 1. Identify the QTL on mouse chromosome 3, A1-A3 (HIVAN1) underlying susceptibility to renal failure by generating additional mapping cohorts and congenic strains trapping this QTL, followed by detailed analysis of the meiotic interval, haplotypes structure and sequence. These analyses will be complemented by whole kidney gene expression studies in specific aim 2. 2. Perform gene expression analysis of the HIV-1 transgenic mice with contrasting susceptibility to HIV associated nephropathy (TgFVB, F1 hybrids and congenic strains) to obtain molecular characterization of renal disease and identify gene expression phenotypes that correlate with renal disease in this model. Differentially expressed genes will also help prioritize positional candidates mapped by linkage analysis. 3. Perform a genome wide analysis of linkage to identify additional QTLs controlling gene expression and renal disease in HIVAN in two backcross cohort of (TgFVB X BALB) X TgFVB and (TgFVB X B6) X TgFVB mice. Linkage the same interval in multiple crosses will be complementary as they may identify common shared haplotypes that will assist in QTL identification. We will next use SNP genotyping, computational and bioinformatics tools to synthesize the data from the above studies in order to identify gene(s) underlying nephropathy and HIV mediated renal injury.
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