ConProject-003

需要验证的假设是，HIV-1感染肾上皮是一种必需的疾病，但不足以诱发疾病。负责易感性和进展的遗传因素可能在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chr03上的QTL，该QTL在存在HIV-1转基因的情况下使小鼠模型的菌株易感性发展为HIV-1，以确定来自其他菌株的其他修饰位点，并结合项目#3，确定在HIV感染响应中差异表达的候选基因，这些候选基因也位于绘制的间隔内。此外，我们假设其发病机制源于直接肾脏感染、病毒基因（特别是nef）的表达、诱导宿主基因的表达以及nef与宿主信号通路的相互作用。项目#2将确定HIV-1感染肾上皮与表型HIVAN产生的关系，与其他非HIVAN但艾滋病相关的肾脏疾病形成对比。此外，项目#2将探索携带HIV-1的隔室，支持其复制和遗传分化，并考虑nef在发病机制中所起的作用。此外，项目#2将确定nef基因多态性对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将共同解决导致病理信号级联的nef表位。最后，项目#3将探讨足细胞和小管上皮细胞的异常宿主基因表达在HIV感染反应中的作用。与项目#1一起，项目#3将确定确定宿主对hiv易感性的潜在候选基因，以及确定肾脏发病途径。这些研究的结果将有助于更好地了解hiv的发病机制、艾滋病的发病机制、适当的治疗策略以及黑人肾脏疾病的易感性。

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 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 nef with 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 nef gene 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 nef that 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.