GENETIC STUDIES OF HIV ASSOCIATED NEPHROPATHY

HIV 相关肾病的遗传学研究

• 批准号: 6862318
• 负责人: ALI G GHARAVI
• 金额: $ 21.24万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6862318
• 关键词: HIV infections; bioinformatics; gene expression profiling; genetic mapping; genetic screening; genetic strain; genetic susceptibility; genetically modified animals; kidney disorder; laboratory mouse; linkage mapping; quantitative trait loci; renal failure; single nucleotide polymorphism

The aims of this project are to apply genomic approaches to delineate mechanisms underlying the development of HIV associated nephropathy (HIVAN), one of the most common causes of renal failure. Using HIV-1 transgenic mice (TgFVB), we have already identified one QTL mediating severity of renal disease on mouse chromosome 3. We propose to identify this QTL and other QTL's controlling the development of renal disease through analysis of congenic strains and additional mapping cohorts, using a combination meiotic mapping, haplotype resolution, gene expression studies and sequence data mining. The specific aims of this project are: 1. Identify the QTL on mouse chromosome 3, A1-A3 (HIVAN1) underlying susceptibility to renal failure by generating additional mapping cohorts and congenic strains trapping this QTL, followed by detailed analysis of the meiotic interval, haplotypes structure and sequence. These analyses will be complemented by whole kidney gene expression studies in specific aim 2. 2. Perform gene expression analysis of the HIV-1 transgenic mice with contrasting susceptibility to HIV associated nephropathy (TgFVB, F1 hybrids and congenic strains) to obtain molecular characterization of renal disease and identify gene expression phenotypes that correlate with renal disease in this model. Differentially expressed genes will also help prioritize positional candidates mapped by linkage analysis. 3. Perform a genome wide analysis of linkage to identify additional QTLs controlling gene expression and renal disease in HIVAN in two backcross cohort of (TgFVB X BALB) X TgFVB and (TgFVB X B6) X TgFVB mice. Linkage the same interval in multiple crosses will be complementary as they may identify common shared haplotypes that will assist in QTL identification. We will next use SNP genotyping, computational and bioinformatics tools to synthesize the data from the above studies in order to identify gene(s) underlying nephropathy and HIV mediated renal injury.

该项目的目的是应用基因组方法来描述艾滋病毒相关肾病（Hivan）发展的机制，这是肾衰竭最常见的原因之一。使用HIV-1转基因小鼠（TGFVB），我们已经确定了一个QTL介导的小鼠染色体肾脏疾病的严重程度。我们建议通过使用优先菌株的分析和其他绘图群进行分析，并使用量化的量化量级构图，确定了比较型号的研究，从而确定了该QTL和其他QTL控制肾脏疾病的发展。该项目的具体目的是：1。在小鼠3，A1-A3（HIVAN1）上识别QTL，通过产生额外的映射队列和杂乱的菌株来诱捕此QTL，然后详细分析减少间隔，单倍型结构和序列，通过产生额外的映射队列和一个友好的菌株来确定肾衰竭的易感性。在特定目标2中，全肾脏基因表达研究将补充这些分析。 2。对HIV-1转基因小鼠进行基因表达分析，对HIV相关肾病的敏感性（TGFVB，F1杂种和先天性菌株）进行分子 肾脏疾病的表征并确定与该模型中肾脏疾病相关的基因表达表型。差异表达的基因还将有助于优先考虑通过链接分析映射的位置候选者。 3。对链接进行基因组广泛的分析，以鉴定在两个反向交叉队列中控制基因表达和肾脏疾病的其他QTL（TGFVB x BALB）X TGFVB和（TGFVB X B6）X TGFVB小鼠。链接在多个十字中相同的间隔将是互补的，因为它们可以识别有助于QTL识别的常见共享单倍型。接下来，我们将使用SNP基因分型，计算和生物信息学工具来合成上述研究的数据，以鉴定肾病和HIV介导的肾损伤的基因。