Transgene Induced HIV-Associated Nephropathy

转基因诱发的 HIV 相关肾病

• 批准号: 6696131
• 负责人: VINCENT H GATTONE
• 金额: $ 21.74万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696131
• 关键词: AIDS; African American; cellular pathology; gene targeting; genetic strain; genetic susceptibility; genetically modified animals; glomerulosclerosis; immunocytochemistry; kidney disorder; laboratory rat; molecular pathology; pathologic process; phenotype; quantitative trait loci; racial /ethnic difference; tissue /cell culture; virus cytopathogenic effect

DESCRIPTION (provided by applicant): Human Immunodeficiency Virus Associated Nephropathy (HIVAN) is a devastating complication of HIV-1infection in African-Americans. The pathology of HIVAN includes a focal segmental glomerulosclerosis (FSGS) as well as tubulo interstitial changes (microcysts and chronic inflammatory infiltrate) although FSGS correlates best with the loss of renal function. Little is known regarding the pathogenesis of HIVAN, which is due to the paucity of models with which to evaluate the early stages of the condition. We believe that both infectious and transgene-induced models of HIVAN are needed to provide the necessary understanding of HIVAN to develop interventional therapies. Recent data clearly suggest HIVAN is caused by the infection of renal epithelia by HIV. The infection of the glomerular epithelial cells (GECs), which controls glomerular filtration, is thought to play a critical role in the development of HIVAN by inducing a dedifferentiation of these highly specialized cells. We hypothesize that the expression of HIV proteins such as Tat and Env stimulate this phenotypic change in GECs, which results in the development of FSGS. Recently, a new rat HIV-transgenic model that develops glomerulosclerosis was described. In the present application we aim to: 1) characterize the developmental stages of the FSGS in these rats at both a morphological and molecular level; 2) identify modifier gene loci that may provide insight into the obvious racial predilection of HIVAN in African-Americans; and 3) identify factors that might contribute to the progression of HIVAN by developing a GEC culture assay system in which we can assess both HIV gene expression and changes in the GEC phenotype. By studying this HIV-transgenic rat, we should be able to identify additional factors that contribute to the HIV-induced phenotype in GECs and provide new information that will lead to a rational treatment for HIVAN.

描述（由申请人提供）：人类免疫缺陷病毒相关肾病 (HIVAN) 是非洲裔美国人感染 HIV-1 的一种毁灭性并发症。 HIVAN 的病理包括局灶节段性肾小球硬化 (FSGS) 以及肾小管间质改变（微囊和慢性炎症浸润），尽管 FSGS 与肾功能丧失的相关性最好。由于缺乏评估该病早期阶段的模型，人们对 HIVAN 的发病机制知之甚少。我们认为，需要感染性和转基因诱导的 HIVAN 模型来提供对 HIVAN 的必要了解，以开发介入疗法。最近的数据明确表明 HIVAN 是由 HIV 感染肾上皮细胞引起的。控制肾小球滤过的肾小球上皮细胞 (GEC) 的感染被认为通过诱导这些高度特化的细胞去分化，在 HIVAN 的发展中发挥关键作用。我们假设 HIV 蛋白（如 Tat 和 Env）的表达刺激 GEC 的这种表型变化，从而导致 FSGS 的发展。最近，描述了一种出现肾小球硬化症的新的大鼠 HIV 转基因模型。在本申请中，我们的目标是：1）在形态学和分子水平上表征这些大鼠中 FSGS 的发育阶段； 2) 确定修饰基因位点，可以深入了解非裔美国人中 HIVAN 的明显种族偏好； 3) 通过开发 GEC 培养测定系统来确定可能导致 HIVAN 进展的因素，在该系统中我们可以评估 HIV 基因表达和 GEC 表型的变化。通过研究这种 HIV 转基因大鼠，我们应该能够确定导致 GEC 中 HIV 诱导表型的其他因素，并提供新的信息，从而对 HIVAN 进行合理的治疗。