Physiological Genomics of Hypertensive Renal Disease

ESRD是美国的一个主要健康问题，发病率不断上升。高血压和糖尿病 占ESRD的67%以上。这些关联并不被理解，但许多人认为， 肾衰竭的最终共同途径，不依赖于诱导剂或疾病。不是每个人都有 高血压或糖尿病发展为终末期肾病，我们证明了肾衰竭基因可能是 与高血压无关。我们有一个全面的研究计划，利用遗传学，基因组学， 研究高血压、糖尿病和肾脏疾病易感基因的相互作用。的 这项计划的目标是确定高血压相关ESRD易感性的基因， 识别相关的生理通路。我们提出三个具体目标： 1.证明Rab 38是Rf-2基因。我们最近报道Rab 38是Rf-2基因。我们假设 Rab 38基因具有多效性作用，并有助于FHH大鼠蛋白尿的发生。 我们将通过a）研究近端小管原代培养物中的白蛋白摄取和B）用 转基因“拯救”。 2.完成Rf-1基因和Rf-4基因的定位克隆和验证。Rf-1 QTL为 FHH中ESRD的显性基因座。重要的是，该位点与Rf-4具有强相互作用。我们有 将Rf-1间隔降低到2.5 cM，Rf-4间隔降低到0.8 cM，整个区域已被 在BN大鼠中测序到接近完成的水平。我们将使用亚同源基因研究每个基因座， 生理学研究和序列比较以鉴定两个基因座中的致病基因。因果基因将 在FHH基因组背景下通过大鼠转基因拯救进行验证。 3.启动Rf-3的定位克隆。我们已经证明了我们通过位置克隆基因的能力。 我们发现，Rf-3也在与小鼠和人类肾脏疾病相关的区域，就像Rf-1，-2， -4。我们将利用现有的双（Rf-1+3）同源株产生重叠同源株， Rf-3间隔。我们有信心，我们要么找到基因，要么将间隔缩小到少数 基因的数量。

ESRD is a major health problem in the United States, with increasing incidence. Hypertension and diabetes account for more than 67% of ESRD. These associations are not understood, but many believe there is a final common pathway for renal failure independent of inducing agent or disease. Not everyone with hypertension or diabetes develops ESRD, and we demonstrated that renal failure genes could be independent of hypertension. We have a comprehensive research program utilizing genetics, genomics, transgenics to study the interactions of hypertension, diabetes and renal disease susceptibility genes. The goal of this proposal is to identify genes responsible for susceptibility to hypertension-related ESRD, and to identify the physiological pathways involved. We propose three specific aims: 1. Validate that Rab38 is the Rf-2 gene. We recently reported Rab38 to be the Rf-2 gene. We hypothesize that the Rab38 gene has pleiotropic effects and contributes to the development of proteinuria in FHH rats. We will test this hypothesis by a) studying albumin uptake in primary cultures of proximal tubule and b) with transgenic "rescue". 2. Complete the positional cloning and validation of the Rf-1 gene and Rf-4 gene. The Rf-1 QTL isthe dominant locus for ESRD in the FHH. Importantly, this locus has a strong interaction with Rf-4. We have reduced both the Rf-1 interval to 2.5 cM and the Rf-4 interval to 0.8cM, and the entire region has been sequenced in BN rats to a nearly finished level. We will investigate each locus using sub-congenics, physiological studies and sequence comparison to identify the causal gene(s) in both loci. Causal genes will be validated by rat transgenic rescue in the FHH genome background. 3. Initiate the positional cloning of Rf-3. We have demonstrated our ability to clone genes by position. We show that Rf-3 is also in a region linked to renal disease in mouse and human as is the case for Rf-1,-2, and -4. We will use the existing double (Rf-1+3) congenic strain to generate the overlapping congenics in the Rf-3 interval. We are confident that we will either find the gene or narrow down the interval to a handful of genes when we complete the term of this grant.