ConProject-003

需要检验的假设是，HIVAN是一种疾病，在这种疾病中，需要HIV-1感染肾上皮，但不足以诱发疾病。负责易感性和进展的遗传因素可能位于病毒进入事件的下游。为了接近这一点，我们建议识别小鼠chr03上的QTL，该QTL是在存在HIV-1转基因的情况下发展HIVAN的小鼠模型的毒株敏感性的基础上的，识别来自其他毒株的其他修饰基因，并结合项目#3，定义与HIV感染相关的差异表达的候选基因，这些基因也位于映射的间隔内。此外，我们假设发病机制源于直接肾脏感染、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HIV-1感染肾上皮细胞与表型HIVAN发生的关系，与其他非HIVAN但与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病毒的区段，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基因的多态对HIVAN表型表达的影响。项目4将探索nef激活足细胞内信号通路从而导致疾病的机制。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将解决足细胞和肾小管上皮细胞宿主基因异常表达在应对艾滋病毒感染中的作用。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，并定义肾脏发病的途径。这些研究的结果将有助于更好地了解HIVAN的发病机制、艾滋病的发病机制、适当的治疗策略，以及对一般黑人肾脏疾病易感性的洞察。

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.