Genetic Analysis of Renal Disease in SHR and Dahl S Rats

SHR 和 Dahl S 大鼠肾病的遗传分析

• 批准号: 6530759
• 负责人: JOHN P RAPP
• 金额: $ 25.73万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-08 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6530759
• 关键词: animal breeding; animal population genetics; blood pressure; chronic renal failure; genetic strain; genetic susceptibility; hypertension; laboratory rat; linkage mapping; proteinuria; quantitative trait loci; spontaneous hypertensive rat

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.

描述（来自申请的逐字描述）：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具有 复杂的遗传成分。为了了解ESRD的遗传原因，我们 建议确定负责发展的遗传成分， Dahi盐敏感（S）大鼠中快速进展的肾脏病理学。做 这一点，分离群体来自交叉S大鼠自发 高血压大鼠（SHR）。这两种菌株明显不同 与蛋白尿和肾脏疾病进展有关。年轻的S大鼠有 非常高的蛋白尿和迅速发展的肾脏病变;年轻的SHR显示 基本上最低限度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SHR之间蛋白尿显著差异的QTL 将在年轻时开始进行，并在随后的时间点进行， F2（SHR × S）群体饲喂低盐饮食，以最大限度地减少 高血压 区分S和SHR大鼠的血压QTL已经被 在高盐饮食中定义为位于大鼠3、6、8和9号染色体上。的 这些血压QTL与进行性血压QTL的关系 蛋白尿/肾脏疾病将通过确定 在高盐饲料饲养的F2（SHR × S）群体中，这两个性状的QTL。 其中一个区分S和SHR的血压QTL可能与S和SHR的血压相关 与S和S之间血管平滑肌反应的显著差异有关， SHR转换为离子钴。这是一个孟德尔性状，它将被放置在大鼠 基因图谱，以确定其与血压和蛋白尿的关系 QTL。 最后，将启动同类菌株的开发， QTL，特别是蛋白尿/肾病的QTL，由上述定义 遗传分析这些同源株系是以后优良遗传所必需的 定位和最终的基因鉴定。