Program Project: The Pathogenesis of HIV-Associated Nephropathy

项目项目：HIV相关肾病的发病机制

基本信息

批准号：
8724823
负责人：
PAUL Evan KLOTMAN
金额：
$ 0.39万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-30 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8724823
关键词：
AIDS-Associated Nephropathy Accounting Acquired Immunodeficiency Syndrome Address African Autopsy Binding Biopsy Brain Candidate Disease Gene Caucasians Caucasoid Race Cell Proliferation Cells Collaborations Congenic Strain DNA Data Development Disease Disease susceptibility Dissection Epithelial Epithelial Cells Epithelium Epitopes Etiology Event Gene Expression Generations Genes Genetic Genetic Drift Genetic Polymorphism Goals HIV HIV Envelope Protein gp120 HIV Infections HIV-1 Haplotypes In Situ In Vitro Infection Inflammatory Kidney Kidney Diseases Knockout Mice Lasers Lead Length Maps Mediating Modeling Molecular Mus Mutation Names Nephrosis Oligonucleotides Pathogenesis Pathway interactions Patients Peripheral Blood Mononuclear Cell Phenotype Play Predisposition Production Protein Family Protein Isoforms Proteins Quantitative Trait Loci Reagent Renal glomerular disease Role Sequence Analysis Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA Specificity Testing Tissues Transgenes Transgenic Mice Transgenic Model Transgenic Organisms Tubular formation Variant Viral Viral Genes Virus Replication Work cohort disease phenotype gene interaction genome-wide glomerular basement membrane improved in vivo insight interstitial leucine-rich repeat protein member mutant nef Genes novel podocyte pressure prevent programs renal epithelium repository research study response synaptopodin therapeutic target

项目摘要

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 with 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 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.

要检验的假设是，希文是一种疾病，其中需要肾上皮的HIV-1感染，但不足以诱导这种疾病。负责敏感性和进展的遗传因素可能是病毒进入事件的下游。为此，我们建议鉴定小鼠ChR03上的QTL，即在存在HIV-1转基因的情况下鼠模型的应变易感性，以确定来自其他菌株的其他修饰基因座，并与项目＃3结合使用，并结合Project＃3，定义候选基因在对Hiv Inviception的响应中也不同地表达了hiv在鼠标范围内，该基因在hiv感染中也响应于Mappaped Interpaper Interpaper Interpaper。此外，我们假设发病机理源自直接的肾脏感染，病毒基因的表达（特别是NEF），诱导的宿主基因表达以及Nefwith宿主信号通路的相互作用。项目＃2将定义肾上皮的HIV-1感染与表型Hivan的产生，与其他非Hivan相反，但与其他非Hivan相比，但艾滋病相关的肾脏疾病。此外，项目＃2将探索具有HIV-1的隔室，支持其复制和遗传差异，并考虑NEF在发病机理中的作用。此外，项目＃2将确定NEF基因对Hivan表型表达的多态性的影响。项目＃4将探索NEF激活导致疾病的足细胞中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的表位。最后，项目＃3将解决对HIV感染的异常宿主基因表达和肾小管上皮细胞的作用。与项目＃1一起，项目＃3将定义潜在的候选基因，这些基因将宿主敏感性定义为Hivan，并定义肾脏发病机理的途径。这些研究的结果将提供对Hivan发病机理，有助于发病机理，适当治疗的适当策略以及对黑人一般肾脏疾病敏感性的见解的提高理解。