Physioligical Genomics of Hypertensive Renal Disease

描述(由申请人提供)： 终末期肾病(ESRD)在美国仍然是一个主要的健康问题 各州的发病率在一年多的时间里一直在稳步上升 十年。超过67%的ESRD与高血压和/或 糖尿病。这些关联的原因尚不清楚。然而，还有 越来越多的证据表明，易感基因可能起着重要作用 在确定一名患者时？S易患终末期肾病。我们已经开发出一种 全面的研究计划，包括遗传学、基因组学、大鼠转基因 和基于机制的生理学来研究复杂的相互作用 高血压与肾脏疾病易感基因。在此，我们建议 将这些工具集中在以下具体目标上：1.完成 RF-1基因的克隆。我们发现了这个重要的QTL，并提出了 结合作图和比较基因组学来定位特定的基因。2. 利用基因芯片确定参与肾脏疾病过程的途径 技术通过鉴定正常和正常组织中差异表达的基因 随着疾病肾脏的发展，我们将看到ESRD基因是如何 在疾病过程中，表达会发生改变。3.测试我们的假设 RF-1由于缺乏肌源性张力而导致肾脏自我调节受损， 导致肾小球高血压和肾脏损伤。我们还将继续追查 QTL S Rf-2、-3和-5的机理研究4.研究Rf-1基因座 通过构建携带YAC的转基因大鼠。这将允许直接测试 YAC内的任何基因。转基因技术也将用于验证RF-1。 5.利用比较基因组学研究人类RF-1区的同源基因 人类的基因和其他候选基因。使用受影响/未受影响的人 同胞，我们将使用SNP和序列分析来确定个体 表现出ESRD与序列变异显著相关 候选基因。

DESCRIPTION (provided by applicant): End-stage renal disease (ESRD) remains a major health problem in the United States, with an incidence that has been increasing steadily for more than a decade. More than 67% of ESRD is associated with hypertension and/or diabetes. The causes for these associations are not known. However, there is increasing evidence that susceptibility genes are likely to play a major role in determining a patient?s predisposition to ESRD. We have developed a comprehensive research program including genetics, genomics, rat transgenics and mechanism-based physiology to study the complex interaction between hypertension and susceptibility genes for renal disease. Here we propose to focus these tools on the following specific aims: 1. Complete the positional cloning of the Rf-1 gene. We identified this important QTL and propose to combine mapping and comparative genomics to locate the specific gene. 2. Determine pathways involved in the renal disease process using microarray technology. By identifying genes differentially expressed in normal and diseased kidney over the time course of ESRD development, we will see how gene expression is modified in the disease process. 3. Test our hypothesis that Rf-1 causes impaired renal autoregulation due to a lack of myogenic tone, resulting in glomerular hypertension and renal damage. We will also pursue mechanism-based studies of the QTL?s Rf-2, -3 and -5. 4. Study the Rf-1 locus by constructing transgenic rats carrying YACs. This will allow a direct test of any genes within the YAC. Transgenics will also be used to validate Rf-1. 5. Use comparative genomics to study human homologue of the Rf-1 region, Rf-1 gene and other candidate genes in humans. Using affected/unaffected human sibpairs, we will use SNP and sequence analysis to determine if individuals exhibiting ESRD show a significant association with sequence variants in candidate genes.