The Pathogeneis of HIV-Associated Nephropathy

待检验的假设是，HIVAN是一种需要肾上皮HIV-1感染但不足以诱发疾病的疾病。导致易感性和进展的遗传因素可能是病毒进入事件的下游。为了解决这个问题，我们建议确定小鼠chr 03上的QTL，该QTL是小鼠模型在HIV-1转基因存在下发展HIVAN的菌株易感性的基础，以确定来自其他菌株的其他修饰位点，并结合Nith项目#3，定义响应于HIV感染而差异表达的候选基因，这些基因也位于映射的间隔内。此外，我们假设，发病机制来自直接的肾脏， 感染、病毒基因（特别是nef）的表达、宿主基因的诱导表达以及nef与宿主信号通路的相互作用。项目#2将确定肾上皮的HIV-1感染与表型HIVAN产生的关系，与其他非HIVAN但与AIDS相关的肾脏疾病形成对比。此外，项目#2将探索窝藏HIV-1的隔间，支持其复制和遗传差异，并考虑nef在发病机制中的作用。此外，项目#2将确定nefgene的多态性对HIVAN表型表达的影响。项目#4将 探索nef激活足细胞中导致疾病的细胞内信号通路的机制。项目#2和#4将一起解决导致病理信号级联的nef表位。最后，项目#3将解决足细胞和肾小管上皮细胞的异常宿主基因表达在响应HIV感染中的作用。与项目#1一起，项目#3将定义潜在的候选基因，这些基因定义宿主对HIVAN的易感性以及定义肾脏发病机制的途径。这些研究的结果将有助于加深对HIVAN发病机制、艾滋病发病机制、 治疗策略，以及对黑人肾脏疾病易感性的认识。

The hypothesis to be tested is that HIVAN is a disease in which HIV-1 infection of renal epithelium is required but not sufficient to induce the disease. Genetic factors responsible for susceptibility and progression are likely to be downstream of the viral entry event. To approach this, we propose to identify the QTL on mouse chr03 underlying the strain susceptibility of the murine model to develop HIVAN in the presence of an HIV-1 transgene, to identify additional modifying loci from other strains, and, in combination Nith Project #3, define candidate genes differentially expressed in response to HIV infection that are also located within mapped intervals. Furthermore, we hypothesize that pathogenesis derives from direct renal infection, expression of viral genes (specifically nef), induced expression of host genes, and interactions of nefwith host signaling pathways. Project #2 will define the relationship of HIV-1 infection of renal epithelium with the generation of phenotypic HIVAN, in contrast to other non-HIVAN but AIDS associated renal diseases. In addition, Project #2 will explore the compartments that harbor HIV-1, support its replication and genetic divergence, and consider the role that nef plays in pathogenesis. In addition, Project #2 will determine the impact of poymorphisms of the nefgene in phenotypic expression of HIVAN. Project #4 will explore the mechanisms by which nef activates intracellular signaling pathways in podocytes that lead to disease. Projects #2 and #4 will together address epitopes of nefthat lead to a pathological signal cascade. Finally, Project #3 will address the role of aberrant host gene expression of podocytes and tubular epithelial cells in response to HIV infection. Together with Project #1, Project #3 will define potential candidate genes that define host susceptibiliity to HIVAN as well as define pathways of renal pathogenesis. Results from these studies will provide improved understanding of HIVAN pathogenesis, AIDS pathogenesis, appropriate strategies for therapy, and insights into renal disease susceptibility of Blacks in general.