HOST FACTORS IN PATHOGENESIS OF HIV ASSOCIATED NEPHROPATHY

HIV相关肾病发病机制中的宿主因素

• 批准号: 6862323
• 负责人: PAUL Evan KLOTMAN
• 金额: $ 29.56万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6862323
• 关键词: HIV infections; apoptosis; cell proliferation; epithelium; genetic susceptibility; genetically modified animals; host organism interaction; human immunodeficiency virus 1; human tissue; kidney disorder; laboratory mouse; podocyte; protein structure function; renal failure; renal tubule; virus genetics; virus infection mechanism; virus protein

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.

HIV-1相关性肾病（HIV-1 associated nephropathy， HIVAN）是一种由HIV-1直接感染肾小球和小管上皮引起的疾病。由于这种感染，足细胞和小管上皮细胞表现出各种表型变化，包括去分化、增殖增加和凋亡增加。我们已经确定了新的宿主途径来应对HIV-1感染，其中包括Podocan，一种富含亮氨酸的小重复蛋白家族的新成员和Sidekick，一种在指定视网膜感光细胞命运中很重要的基因。在目前的提案中，我们建议探索这两个基因在人类HIVAN和转基因小鼠模型中的表达。为了更好的