RNA profiling of HIV-associated nephropathy in patients with the MYH9 risk allele

MYH9 风险等位基因患者 HIV 相关肾病的 RNA 分析

• 批准号: 8046224
• 负责人: PAUL Evan KLOTMAN
• 金额: $ 195万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046224
• 关键词: AIDS-Associated Nephropathy; Address; African; African American; Alleles; Area; Biological; Complex; Data; Dilatation - action; Disease; Disease Progression; Down-Regulation; End stage renal failure; Environmental Risk Factor; Face; Focal Segmental Glomerulosclerosis; Functional RNA; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genomics; Goals; HIV; HIV Infections; HIV-1; Health; Human; Immune response; Individual; Infection; Inflammation; Kidney Diseases; Laboratories; Literature; Mediating; MicroRNAs; Modeling; Myosin Heavy Chains; Nonmuscle Myosin Type IIA; Pathogenesis; Patients; Predisposition; Publishing; RNA; Research; Risk; Systems Biology; Transcript; Tubular formation; Virus; genome-wide; glomerulosclerosis; high throughput technology; insight; interstitial; next generation; non-muscle myosin; podocyte; protein function; response

DESCRIPTION (provided by applicant): This project addresses the "Applying Genomics and Other High Throughput Technologies" thematic area. HIV-associated nephropathy (HIVAN) is a unique disease that results from the interplay of environmental factors (HIV), host responses to the virus, and a genetic predisposition, primarily in individuals of African descent. As a result of these complex interactions, a number of maladaptive biological responses occur that produce the collapsing glomerulosclerosis with pseudocrescent formation, microcystic tubular dilatation, and prominent interstitial inflammation that we recognize pathologically as HIVAN. Recent Genome-wide analyses have identified a strong association of the gene MYH9, which encodes non-muscle myosin heavy chain IIA (Myosin-9), with idiopathic and HIV-associated FSGS in African-Americans. Despite the strong association of MYH9 polymorphisms with the risk of HIVAN, two copies of the MYH9 E-1 risk allele is not sufficient for nephropathy. Additionally, there are no data on the functional consequence of MYH9 risk alleles on Myh9 transcript or protein function. To understand how the MYH9 risk allele in combination with HIV-1 infection promotes alteration of the podocyte regulatory network we plan to use next generation sequencing to explicitly define the entire RNA- transcriptome and small non-coding RNAs and compare this between individuals with and without the risk allele. We will use systems biology models to integrate new data with existing data from our laboratory and in the published literature. Our goals are: 1) Determine variability in podocyte transcriptome and regulatory networks in HIV-infected and control human podocytes from patients with or without the MYH9 risk allele when environmental factors are controlled. We hypothesize that even if the environmental factors are controlled, there will still be a variable response to HIV-infection. We will also determine if there is differential miRNA expression in HIV-1 in podocytes with or without the MYH9 risk allele. 2) Determine the mechanism by which MYH9 is downregulated. PUBLIC HEALTH RELEVANCE: The proposed research has the potential to significantly impact the health of people of African descent, who face a disproportionate burden of HIV infection and end-stage renal disease. Findings from the proposed research are likely to provide insights into the increased susceptibility to kidney disease and end-stage renal disease among people of African descent.

描述（由申请人提供）：该项目涉及“应用基因组学和其他高通量技术”的主题领域。HIV相关性肾病（HIVAN）是一种独特的疾病，由环境因素（HIV）、宿主对病毒的反应和遗传易感性的相互作用引起，主要发生在非洲裔个体中。由于这些复杂的相互作用，发生了许多适应不良的生物反应，产生了塌陷的肾小球硬化伴假性肾小球形成、微囊肾小管扩张和突出的间质炎症，我们在病理学上将其识别为HIVAN。最近的全基因组分析已经确定了基因MYH 9（编码非肌肉肌球蛋白重链IIA（肌球蛋白-9））与非裔美国人的特发性和HIV相关FSGS的强相关性。尽管MYH 9多态性与HIVAN风险密切相关，但两个MYH 9 E-1风险等位基因拷贝不足以导致肾病。此外，没有关于MYH 9风险等位基因对Myh 9转录物或蛋白质功能的功能后果的数据。为了了解MYH 9风险等位基因与HIV-1感染的结合如何促进足细胞调控网络的改变，我们计划使用下一代测序来明确定义整个RNA转录组和小的非编码RNA，并在有和没有风险等位基因的个体之间进行比较。我们将使用系统生物学模型将新数据与我们实验室和已发表文献中的现有数据整合在一起。我们的目标是：1）当控制环境因素时，确定来自具有或不具有MYH 9风险等位基因的患者的HIV感染和对照人类足细胞中足细胞转录组和调控网络的变异性。我们假设，即使环境因素得到控制，仍然会有一个可变的艾滋病毒感染的反应。我们还将确定在有或没有MYH 9风险等位基因的足细胞中HIV-1是否存在差异miRNA表达。2)确定MYH 9下调的机制。 公共卫生相关性：拟议的研究有可能对非洲人后裔的健康产生重大影响，他们面临着不成比例的艾滋病毒感染和终末期肾病负担。拟议研究的结果可能有助于深入了解非洲人后裔对肾病和终末期肾病的易感性增加的问题。