Transgene Induced HIV-Associated Nephropathy

点击翻译按钮获取中文摘要

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.