HIV-1 associated nephropathy (HIVAN) is a disease of the glomerular and tubular epithelium caused by direct infection of these cellular compartments by HIV-I. As a result of this infection, podocytes and tubular epithelial cells demonstrate a variety of phenotypic changes, including de-differentiation, increased proliferation, and increased apoptosis. We have identified novel host pathways responding to HIV-1 infection that include Podocan, a novel member of the small leucine-rich repeat protein family and Sidekick, a gene that is important in specifying photoreceptor cell fate in the retina. In the current proposal, we propose to explore the expression of these two genes in human HIVAN and in the transgenic mouse model. To better understand the role of Podocan's endogenous function in vivo and its potential role in renal disease, we will generate Podocan-null mice as well as podocyte over-expressing transgenic mice. To examine the role for Sidekick-1 in HIVAN, we will also overexpress it in podocytes of transgenic mice. Using in vitro assays, we will map the HIV-1 gene product(s) that are responsible for inducing Sidekick-1 expression and investigate the function of Sidekick-1 and 2 in podocytes before and after HIV-1 infection in vitro. And, we will determine the intracellular binding partners for Sidekick-1 and 2. Finally, we propose to characterize the response of human renal tubular epithelial cells to HIV-1 infection using oligonucleotide expression microarrays. This approach will permit us to identify genes that are differentially expressed at specific time points following infection of renal tubular epithelial cells by HIV-1 in vitro. After exploring the effect of HIV-1 infection on proliferation and apoptosis in epithelial cells, we will map the HIV-1 gene(s) responsible for inducing these effects. These studies combined with information from Project #1 will elucidate mechanisms by which HIV-1 induces renal disease in susceptible individuals and should provide insight into the mechanisms of disease progression in Blacks in general.
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