GENETIC FACTORS FOR PROGRESSION OF HIV ASSOCIATED NEPHROPATHY

与许多系统性疾病类似，HIV-1感染会在特定的人群亚群中导致终末期肾病(ESRD)，主要是非裔美国人，因此表明遗传风险因素在肾功能衰竭的发展中起着关键作用。该项目的目的是定位与终末期肾病(ESRD)相关的数量性状基因座(QTL)，重点关注HIV-1相关性肾病(HIVAN)的小鼠模型。为了实现这一目标，Core B将在HIV-1转基因小鼠品系(TG26)和卡他分枝杆菌(MCAST)品系之间提供仔细的表型B2杂交。这个项目将进行QTL的定位。这项工作将是识别导致肾功能衰竭的潜在性状基因座的关键一步。这个项目的功能将解决以下目标：1.鉴定一组160个间隔约10 cM的简单序列长度多态，这些多态在TG26×MCAST杂交中具有信息性。2.对B_2群体中的动物进行基因分型分析，然后进行连锁分析，比较每个性状与跨越小鼠基因组的标记基因座的分离情况。4.利用同源菌株的减数分裂定位精细定位QTL，并通过候选基因分析和定位克隆鉴定与肾功能衰竭相关的基因(S)。人们认为，将计划项目的大部分分子遗传学工作放在一个具有既定专业知识的单一项目中是合乎逻辑的，因为它最大限度地利用了重复任务中使用的人员和设备，如标记开发、基因分型和连锁分析。

Similar to many systemic disorders, HIV-1 infection causes end-stage renal disease (ESRD) in defined population subgroups, primarily African Americans, thereby suggesting that genetic risk factors have a critical role in the development of renal failure. The aim of this project is to map the quantitative trait loci (QTL's) relevant to the development of ESRD by focusing on a murine model of HIV-1 associated nephropathy (HIVAN). To achieve this goal, Core B will provide a carefully phenotyped B2 cross between the HIV-1 transgenic mouse line (Tg26) and M. cataneus (MCAST) strains. This project will perform mapping of QTL's. This effort will constitute a critical step toward identification of underlying trait loci contributing to renal failure. The function of this project will address the following aims: 1. Identification of a screening set of 160 simple sequence length polymorphisms spaced at approximately 10 cM intervals that are informative in the Tg26 x MCAST cross. 2. Genotypic analysis of animals in the B2 cohort followed by analysis of linkage comparing the segregation of each trait to marker loci spanning the mouse genome. 3. Genetic characterization of congenic strains trapping the QTLs identified in aim 2. 4. Fine mapping of the QTL by meiotic mapping of the congenic strains followed by identification of the gene(s) response for the development of renal failure by candidate gene analysis and positional cloning. It is believed that placing performance of much of the molecular genetics of the program project in a single project with established expertise is logical, since it maximizes use of personnel and equipment employed in repetitive tasks such as marker development, genotyping and analysis of linkage.