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相关的肾病（Hivan）是由HIV-I直接感染这些细胞室引起的肾小球和肾小管上皮的疾病。由于这种感染，足细胞和肾小管上皮细胞表现出多种表型变化，包括脱不同，增殖增加和凋亡增加。我们已经确定了对HIV-1感染反应的新型宿主途径，其中包括Podocan，Podocan是小亮氨酸重复蛋白家族和Sidekick的新成员，该基因对于指定视网膜中的感光细胞命运很重要。在当前的建议中，我们建议探索这两个基因在人hivan和转基因小鼠模型中的表达。更好 了解Podocan的内源性在体内的作用及其在肾脏疾病中的潜在作用，我们将产生Podocan-null小鼠以及Podocyte过表达的转基因小鼠。为了检查Hivan中辅助kick-1的作用，我们还将在转基因小鼠的足细胞中过表达它。使用体外测定，我们将绘制负责诱导Sidekick-1表达的HIV-1基因产物，并研究HIV-1感染前和之后在体外感染HIV-1之前和之后的Sidekick-1和2的功能。而且，我们将确定Sidekick-1和2的细胞内结合伙伴。最后，我们建议表征的响应 人肾小管上皮细胞使用寡核苷酸表达微阵列对HIV-1感染。这种方法将使我们能够鉴定出在体外通过HIV-1感染肾小管上皮细胞后在特定时间点差异表达的基因。在探索HIV-1感染对上皮细胞增殖和凋亡的影响之后，我们将绘制负责诱导这些作用的HIV-1基因。这些研究与项目＃1的信息相结合，将阐明HIV-1在易感人群中诱导肾脏疾病的机制，并应深入了解疾病的机制。 一般黑人的进展。