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

描述(申请人提供)：本项目涉及“应用基因组学和其他高通量技术”主题领域。艾滋病毒相关性肾病(HIVAN)是一种独特的疾病，它是环境因素(艾滋病毒)、宿主对病毒的反应和遗传易感性相互作用的结果，主要发生在非洲裔个人中。由于这些复杂的相互作用，发生了许多不适应的生物反应，产生了塌陷性肾小球硬化，伴有假新月体形成、微囊性肾小管扩张和突出的间质炎症，我们在病理学上将其称为HIVAN。最近的全基因组分析发现，编码非肌肉肌球蛋白重链IIA(myosin-9)的Myh9基因与非洲裔美国人的特发性和HIV相关的FSGS有很强的关联。尽管Myh9基因多态性与HIVAN的风险有很强的相关性，但Myh9 E-1风险等位基因的两个副本不足以导致肾病。此外，还没有关于Myh9风险等位基因对Myh9转录本或蛋白质功能的功能影响的数据。为了了解Myh9风险等位基因与HIV-1感染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，并在具有和不具有该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相结合。我们的目标是：1)确定HIV感染者足细胞转录组和调控网络的变异性，并在控制环境因素的情况下控制具有或不具有Myh9风险等位基因的患者的足细胞。我们假设，即使环境因素得到控制，对艾滋病毒感染的反应仍然是可变的。我们还将确定在带有或不带有Myh9风险等位基因的足细胞中，HIV-1中是否存在miRNA的差异表达。2)确定Myh9下调的机制。 公共卫生相关性：拟议的研究有可能显著影响非洲人后裔的健康，他们面临着艾滋病毒感染和终末期肾脏疾病的不成比例的负担。这项拟议研究的结果可能会对非洲裔人患肾脏疾病和终末期肾脏疾病的易感性增加提供见解。

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.