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）是非洲裔美国人HIV-1感染的一种毁灭性并发症。HIVAN的病理学包括局灶节段性肾小球硬化（FSGS）以及肾小管间质变化（微囊肿和慢性炎症浸润），尽管FSGS与肾功能丧失最相关。关于HIVAN的发病机制知之甚少，这是由于缺乏模型来评估疾病的早期阶段。我们认为，感染性和转基因诱导的HIVAN模型都需要提供必要的理解HIVAN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）的感染被认为通过诱导这些高度特化的细胞的去分化在HIVAN的发展中起关键作用。我们推测HIV蛋白如达特和Env的表达刺激了GEC的这种表型变化，从而导致FSGS的发展。最近，一种新的大鼠HIV转基因模型，发展肾小球硬化症的描述。在本申请中，我们的目的是：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）鉴定修饰基因座，其可以提供对非裔美国人中HIVAN的明显种族偏好的了解;和3）通过开发一种GEC培养检测系统，我们可以评估HIV基因和HIV抗体，GEC表型的表达和变化。通过研究这种HIV转基因大鼠，我们应该能够确定导致GECs中HIV诱导表型的其他因素，并提供新的信息，这将导致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.