GENETIC STUDIES OF HIV ASSOCIATED NEPHROPATHY

这个项目的目的是应用基因组方法来描绘HIV相关性肾病(HIVAN)发展的潜在机制，HIVAN是导致肾功能衰竭的最常见原因之一。利用HIV-1转基因小鼠(TgFVB)，我们已经在小鼠的3号染色体上定位了一个控制肾脏疾病严重程度的QTL。我们建议通过对同源品系的分析和额外的定位队列，结合减数分裂定位、单倍型解析、基因表达研究和序列数据挖掘来鉴定该QTL和其他控制肾脏疾病发展的QTL。本项目的具体目标是：1.通过产生额外的作图队列和捕获该QTL的同源菌株，确定小鼠3号染色体A1-A3(HIVAN1)上的QTL，然后详细分析减数分裂间隔、单倍型结构和序列。这些分析将得到特定目标2的全肾基因表达研究的补充。 2.对对HIV相关肾病易感性不同的转基因小鼠(TgFVB、F1杂交株和同源株)进行基因表达分析，获得分子 确定肾脏疾病的特征，并在该模型中确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的优先顺序。3.在(TgFVB X BALB)X TgFVB和(TgFVB X B6)X TgFVB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额外QTL。连锁多个杂交组合的相同间隔将是互补的，因为它们可以识别共同的共享单倍型，这将有助于QTL的鉴定。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，以确定导致肾病和艾滋病毒介导的肾损伤的基因(S)。

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.