Transgene Induced HIV-Associated Nephropathy

描述(由申请人提供)：人类免疫缺陷病毒相关性肾病(HIVAN)是非裔美国人感染HIV-1的毁灭性并发症。HIVAN的病理包括局灶节段性肾小球硬化(FSGS)和肾小管间质改变(微囊和慢性炎性浸润物)，尽管FSGS与肾功能丧失关系最密切。对HIVAN的发病机制知之甚少，这是由于缺乏评估该疾病早期阶段的模型。我们认为，感染和转基因诱导的HIVAN模型都是必要的，以提供对HIVAN的必要了解，以开发介入治疗。最近的数据清楚地表明，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(GECs)的感染被认为在HIVAN的发展中起着关键作用，因为它诱导了这些高度特化的细胞的去分化。我们假设，TAT和Env等HIV蛋白的表达刺激了GECs的这种表型变化，从而导致FSGS的发展。最近，一种新的大鼠HIV转基因肾小球硬化模型被描述。在目前的应用中，我们的目标是：1)在形态和分子水平上表征这些大鼠的FSGS的发育阶段；2)识别修饰基因位点，可能有助于深入了解非裔美国人中HIVAN的明显种族偏好；以及3)通过建立GEC培养检测系统来识别可能导致HIVAN进展的因素，在该系统中，我们可以评估HIV基因的表达和GEC表型的变化。通过对这只HIV转基因大鼠的研究，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，从而导致HIVAN的合理治疗。

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.