GENETIC STUDIES OF HIV ASSOCIATED NEPHROPATHY

该项目的目的是应用基因组方法来描述HIV相关肾病（HIVAN）发展的潜在机制，HIVAN是肾衰竭的最常见原因之一。利用HIV-1转基因小鼠（TgFVB），我们已经在小鼠3号染色体上确定了一个介导肾脏疾病严重程度的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，确定该QTL和其他控制肾脏疾病发展的QTL。该项目的具体目标是：1。通过产生额外的作图队列和捕获该QTL的同源株，然后详细分析减数分裂间隔、单倍型结构和序列，鉴定小鼠3号染色体A1-A3（HIVAN 1）上潜在的肾衰竭易感性QTL。这些分析将通过特定目标2中的全肾基因表达研究进行补充。 2.对HIV-1转基因小鼠（TgFVB、F1杂种和同源株）进行基因表达分析，以获得对HIV相关肾病具有不同易感性的分子标记物。 在该模型中，研究人员可以鉴定肾脏疾病的特征并鉴定与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通过连锁分析确定位置候选者的优先顺序。3.进行全基因组连锁分析，以在（TgFVB X BALB）X TgFVB和（TgFVB X B6）X TgFVB小鼠的两个回交队列中鉴定控制HIVAN中的基因表达和肾病的另外的QTL。在多个杂交中相同间隔的连锁将是互补的，因为它们可以鉴定共同的共享单倍型，这将有助于QTL鉴定。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。

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.