GENETIC STUDIES OF HIV ASSOCIATED NEPHROPATHY

HIV 相关肾病的遗传学研究

• 批准号: 7480354
• 负责人: ALI G GHARAVI
• 金额: $ 22.58万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480354
• 关键词: AIDS-Associated Nephropathy; Accounting; Adult; African American; Analysis of Variance; Architecture; Backcrossings; Bioinformatics; Blood Urea Nitrogen; Cholesterol; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 9; Clinical; Complement; Complication; Congenic Strain; Data; Development; Diabetes Mellitus; Disease susceptibility; Employee Strikes; End stage renal failure; Gene Expression; Generations; Genes; Genetic; Genome; Genomics; HIV; HIV-1; Hand; Haplotypes; Histologic; Histology; Human Chromosomes; Hybrids; Hypertension; Inbred Strain; Infection; Injury; Kidney; Kidney Diseases; Kidney Failure; Link; Maps; Mediating; Meiosis; Methodology; Modeling; Molecular; Mus; Mutation; Nephrosis; Neuro-Oncological Ventral Antigen 2; Pathologic; Phenotype; Predisposition; Proteinuria; Quantitative Trait Loci; Range; Research Personnel; Resistance; Resolution; SNP genotyping; Scanning; Score; Screening procedure; Sequence Analysis; Serum; Serum Albumin; Severities; Structure; Transgenic Mice; Transgenic Organisms; Variant; cohort; congenic; data mining; genetic linkage analysis; genome-wide analysis; genome-wide linkage; programs; response; tool; transmission process

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 HIV 相关肾病 (HIVAN) 发展的机制，HIVAN 是肾衰竭的最常见原因之一。使用 HIV-1 转基因小鼠 (TgFVB)，我们已经在小鼠 3 号染色体上鉴定出一个介导肾病严重程度的 QTL。我们建议通过分析同源株和其他作图队列，结合减数分裂作图、单倍型解析、基因表达研究和序列数据挖掘，鉴定该 QTL 和其他控制肾病发展的 QTL。该项目的具体目标是： 1. 通过生成捕获该 QTL 的额外定位队列和同源株，鉴定小鼠 3 号染色体 A1-A3 (HIVAN1) 上潜在的肾衰竭易感性 QTL，然后详细分析减数分裂间隔、单倍型结构和序列。这些分析将由具体目标 2 中的全肾基因表达研究进行补充。 2. 对与 HIV 相关肾病易感性对比的 HIV-1 转基因小鼠（TgFVB、F1 杂种和同类株）进行基因表达分析，以获得分子 肾脏疾病的特征并鉴定与该模型中肾脏疾病相关的基因表达表型。差异表达的基因也将有助于优先考虑通过连锁分析映射的候选位置。 3. 在 (TgFVB X BALB) X TgFVB 和 (TgFVB X B6) X TgFVB 小鼠的两个回交队列中进行全基因组连锁分析，以确定控制 HIVAN 基因表达和肾脏疾病的其他 QTL。多个杂交中相同间隔的连锁将是互补的，因为它们可以识别共同的共享单倍型，这将有助于QTL识别。接下来，我们将使用 SNP 基因分型、计算和生物信息学工具来综合上述研究的数据，以确定肾病和 HIV 介导的肾损伤的潜在基因。