PATHOGENESIS OF HIV ASSOCIATED NEPHROPATHY

HIV 相关肾病的发病机制

• 批准号: 6495602
• 负责人: PAUL Evan KLOTMAN
• 金额: $ 22.85万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6495602
• 关键词: HIV infections; chronic renal failure; epithelium; gene expression; genetic markers; genetically modified animals; histopathology; host organism interaction; human immunodeficiency virus 1; kidney cell; kidney function; laboratory mouse; medical complication; molecular pathology; renal tubule; representational difference analysis; site directed mutagenesis; tissue /cell culture; virus cytopathogenic effect; virus genetics

HIV associated neuropathy has emerged as a major epidemic in the end stge renal disease (ESRD) program in the United States. From an occasional oddity observed in the mid 1980s, HIVAN has become the third leading cause of ESRD in Blacks. Unfortunately, unlike many of the infectious complications of HIV that have declined dramatically with highly active antiretroviral therapy (HAART), HIVAN continues to increase in both incidence and prevalence. The explanation for the continued increase in HIVAN likely reflects the disproportionate impact that HIV-1 has had on the Black urban community. With the disproportionate increase in new cases of HIV-1 in Blacks and with the decline in mortality from HAART, there has been an astounding increase in the pool of patients at risk for the development of HIVAN to almost 50% of those patients living with AIDS. Continued advances in our understanding of HIVAN pathogenesis are required to address this epidemic, but much has been learned already. HIV-1 is the primary etiologic agent responsible for HIVAN and the renal glomerular and learned already. HIV-1 is the primary etiologic agent responsible for HIVAN and the renal glomerular and tubular epithelium appears to be the targeted cell type. Recent studies have now revealed that HIV-1 can be detected in renal epithelial cells of HIVAN patients. Furthermore, we have identified a series of epithelial surrogate markers for disease. The purpose of this proposal is to explore the viral-host interactions that lead to pathogenesis. The specific aims are first to develop molecular markers in vitro than accurately reflect pathogenesis in vivo using representation difference analysis (RDA). These markers, along with those already identified, will serve as the readout for mapping which HIV-1 genes are responsible for producing HIVAN. The second aim is to identify the HIV-1 gene product(s) responsible for HIVAN pathogenesis by in vitro minimal combinatorial HIV-1 gene expression necessary for the development of HIVAN pathology in vivo using studies should lead us to the initial pathways of renal pathogenesis as well as identify the downstream effectors of disease. Results will define mechanisms of HIVAN pathogenesis, provide potential targets for therapy, and perhaps most importantly, provide insights into the predisposition of Blacks for renal disease of all causes.

艾滋病毒相关的神经病已成为美国末日肾脏疾病（ESRD）计划的主要流行病。 从1980年代中期偶尔观察到的奇怪之处，Hivan已成为黑人ESRD的第三大主要原因。 不幸的是，与高度活跃的抗逆转录病毒疗法（HAART）急剧下降的HIV的许多感染并发症不同，Hivan的发病率和患病率都在增加。 Hivan持续增加的解释可能反映了HIV-1对黑人城市社区的不成比例影响。 由于黑人新的HIV-1病例的不成比例增加，随着HAART死亡率的下降，HIVAN风险危险的患者库的增加，近50％的艾滋病患者的患者却有所增加。 我们对Hivan发病机理的理解持续发展需要解决这一流行病，但已经学到了很多东西。 HIV-1是负责Hivan和肾肾小球的主要病因学剂，并且已经学到了。 HIV-1是负责Hivan的主要病因，肾肾小球和管状上皮似乎是靶向细胞类型。 最近的研究表明，在Hivan患者的肾上皮细胞中可以检测到HIV-1。 此外，我们已经确定了一系列疾病上皮替代标记。 该建议的目的是探索导致发病机理的病毒宿主相互作用。 比使用表示差异分析（RDA）在体外的特定目的首先是在体外发展分子标记的。 这些标记以及已经确定的标记将作为映射HIV-1基因负责产生Hivan的读数。 第二个目的是通过体外最小组合HIV-1基因表达来鉴定负责HIV-1基因产物，使用研究在体内开发Hivan病理学所必需的必要条件，这应该使我们进入肾脏发病机理的初始途径以及鉴定疾病的下游效应。结果将定义Hivan发病机理的机制，为治疗提供潜在的靶标，也许最重要的是，为黑人倾向的所有原因提供了见解。