Genes That Regulate Progression of Kidney Disease and Its Cardiovascular Effects

描述（由申请人提供）：慢性肾脏疾病（CKD）和蛋白尿是心血管疾病的重要风险因素。CKD患者的高血压、缺血性心脏病、左心室肥厚（LVH）和心力衰竭的患病率不成比例地高于普通人群，即使在调整传统的心血管危险因素后也是如此。重要的是，CKD患者更有可能死于心血管疾病而不是肾衰竭。由于CKD的严重性和影响，2001年，国家糖尿病、消化和肾脏疾病研究所建立了慢性肾功能不全队列（CRIC）研究，以检查CKD患者中CKD和心血管疾病进展的风险因素。流行病学研究表明，有一个强大的遗传因素决定了肾脏疾病的易感性，并由此推断，其相关的心血管风险。我们假设有遗传因素导致CKD的进展及其在心血管系统中的后果。在小鼠中使用肾次全切除术，一种良好建立的CKD模型，我们鉴定了2个调节CKD诱导的高血压的新QTL（Ckdbp1和Ckdbp2）。我们还发现了与血压QTL不同的与心脏肥大（Ckdlvhl）连锁的区域。此外，我们已经确定了一个调节白蛋白尿严重程度的QTL，这是与血压QTL Ckdbp2相同的位点。该项目的目标是确定基因赋予心血管疾病的后果慢性肾脏疾病的易感性。我们将集中在最强的QTL，Ckdbp2和Ckdlvhl精细定位和基因鉴定。用于基因鉴定的方法和技术将包括为每个基因座产生同源小鼠品系、重组后代测试以辅助精细定位、DNA序列分析以鉴定序列变体以及使用mRNA表达分析对候选基因进行优先排序。这些易感基因的鉴定和表征将增加我们对CKD进展及其心血管效应的分子机制的理解，并可能为治疗干预提供靶点。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) and proteinuria are powerful risk factors for cardiovascular disease. The prevalence of hypertension, ischemic heart disease, left ventricular hypertrophy (LVH) and heart failure are disproportionately higher in patients with CKD than in the general population, even after adjustment for traditional cardiovascular risk factors. Importantly, CKD patients are more likely to die of cardiovascular disease than to develop kidney failure. Due to the magnitude and implications of CKD, in 2001, the National Institute of Diabetes, Digestive, and Kidney Disease established the Chronic Renal Insufficiency Cohort (CRIC) Study to examine risk factors for progression of CKD and cardiovascular disease among patients with CKD. Epidemiological studies suggest that there is a strong genetic component determining susceptibility for renal disease, and by inference, for its associated cardiovascular risks. We hypothesize that there are heritable factors that contribute to progression of CKD and its consequences in the cardiovascular system. Using sub-total nephrectomy in the mouse, a well-established model of CKD, we have identified 2 novel QTLs that regulate CKD-induced hypertension (Ckdbpl and Ckdbp2). We have also found an area of linkage with cardiac hypertrophy (Ckdlvhl) that is distinct from the QTLs for blood pressure. In addition, we have identified a QTL that regulate the severity of albuminuria, and this is the same locus found for the blood pressure QTL Ckdbp2. The goal of this project is to identify genes that confer susceptibility to the cardiovascular consequences chronic kidney disease. We will focus on the strongest QTLs, Ckdbp2 and Ckdlvhl for fine mapping and gene identification. The methods and techniques used for gene identification will include generation of congenic mouse strains for each locus, recombinant progeny testing to assist in fine-mapping, DMA sequence analysis to identify sequence variants, and prioritization of candidate genes using mRNA expression analysis. Identification and characterization of these susceptibility genes will increase our understanding of the molecular mechanisms underlying the progression of CKD and its cardiovascular effects, and may provide targets for therapeutic intervention.