Genetic Analysis of Renal Disease in SHR and Dahl S Rats

描述(逐字摘自申请表)：年终末期肾病(ESRD) 人类是一个重要的医学问题，需要昂贵的治疗 透析和肾移植。对人类的研究表明，ESRO有一种 复杂的遗传成分。为了了解终末期肾病的遗传原因，我们 建议定义负责发育的遗传成分 大剂量盐敏感(S)大鼠肾脏病理的快速发展。去做 这是由S大鼠与自发杂交而来的分离种群 将对高血压大鼠(SHR)进行研究。这两种菌株有明显的不同 关于蛋白尿和肾脏疾病的进展。年轻的S大鼠有 极高的蛋白尿和迅速发展的肾脏损害；年轻的自发性高血压 基本上很少的蛋白尿和非常缓慢的肾脏疾病进展 尽管他们有高血压。数量性状的连锁分析 控制S和自发性高血压大鼠蛋白尿显著差异的QTL 将从很小的时候开始表演，也会在 F2(自发性高血压×S)人群饲喂低盐饮食以减少糖尿病的发生 高血压。 区分S大鼠和自发性高血压大鼠的血压QTL已经被 在高盐饮食中定义为驻留在大鼠的第3、6、8和9号染色体上。 这些血压QTL与进展性QTL的关系 蛋白尿/肾脏疾病将通过确定 对饲喂高盐饲料的F_2群体(自交系×S)的这两个性状进行了QTL分析。 区分S和自发性高血压的一个血压QTL可能是相关的 论S与陈冯富珍在血管平滑肌反应上的显著差异 SHR到离子钴。这是孟德尔人的特征，它将被放在老鼠身上 确定其与血压和蛋白尿关系的遗传图谱 QTL。 最后，将启动任何独特的同源菌株的开发 QTL，特别是与蛋白尿/肾脏疾病有关的QTL，由以上定义 基因分析。这些同源菌株是以后优良遗传所必需的 作图和最终的基因鉴定。

DESCRIPTION (Verbatim from the application): End stage renal disease (ESRD) in humans is an important medical problem requiring the expensive treatments of dialysis and renal transplantation. Studies in humans suggest that ESRO has a complex genetic component. In order to understand the genetic causes of ESRD we propose to define the genetic components responsible for the development of the rapidly progressing renal pathology in the Dahi salt sensitive (S) rat. To do this, segregating populations derived from crossing S rats with spontaneously hypertensive rats (SHR) will be studied. The two strains are markedly different with regard to proteinuria and progression of renal disease. Young S rats have very high proteinuria and rapidly develop renal lesions; young SHR show essentially minimal proteinuria and very slow progression of renal disease in spite of their high blood pressure. Linkage analysis for the quantitative trait loci (QTL) controlling the marked difference in proteinuria between S and SHR will be performed starting at a young age and also at successive time points in an F2(SHR X S) population fed a low salt diet to minimize the development of hypertension. The QTL for blood pressure that differentiate S and SHR rats have already been defined on high salt diet as residing on rat chromosomes 3, 6, 8 and 9. The relationship of these blood pressure QTL to the QTL for progressive proteinuria/renal disease will be sought by determining the positions of the QTL for both traits in an F2(SHR X S) population fed high salt diet. One of the blood pressure QTL differentiating S and SHR is likely to be related to the marked difference in the vascular smooth muscle response between S and SHR to ionic cobalt. This is a Mendelian trait and it will be placed on the rat genetic map to determine its relationship to blood pressure and proteinuria QTL. Lastly, the development of congenic strains will be initiated for any unique QTL, especially those for proteinuria/renal disease, defined by the above genetic analysis. These congenic strains are required for later fine genetic mapping and ultimate gene identification.