GENETIC STUDIES OF MINERALOCORTICOID FUNCTION

说明(改编自应用程序) 高血压是美国最常见的疾病之一--出现在 占总人口的20%。它也是发病率和死亡率的主要原因之一。 美国的死亡率，通过其对心脏、脑血管和 肾脏疾病。尽管高血压盛行，但高血压的根本原因(S) 人们对此仍然知之甚少。很明显，有环境和环境因素 易患高血压的遗传性遗传因素； 然而，由于遗传因素的规模较小，识别遗传因素变得困难 许多基因的影响加上叠加的环境因素。一 解决这个问题的方法一直是研究单基因疾病，主要是 影响血压。分子碱基的决定因素 糖皮质激素可治愈的醛固酮增多症，利德尔综合征，巴特综合征， 吉特尔曼综合症和其他疾病[原文如此]极大地增加了我们的 对肾脏生理和肾脏在血压中作用的认识 监管。在这个项目中，我们描述了一种新形式的 由盐皮质激素激活突变引起的孟德尔高血压 受体，远端肾单位中的醛固酮的效应分子。穿过 致病家系的鉴定和突变体的体外分析 受体，我们将弄清突变激活的机制 盐皮质激素受体功能。预计这一信息 将深入了解正常的受体功能，这可能被证明是有用的 药物设计。通过创建这种疾病的小鼠模型，我们希望产生一种 研究多种类固醇激动剂的作用机制和 拮抗剂在体内，也是为了洞察被激活的效果 肾以外组织中的盐皮质激素受体。这个项目是 旨在为校长提供分子和人类遗传学方面的培训 作为一名研究人员，并使他能够在学术肾脏病领域发展事业 关注高血压和肾脏疾病的分子遗传学。

DESCRIPTION (adapted from the application) Hypertension is one of the most common diseases in America--being present in a 20% of the population. It is also one of the leading causes of morbidity and mortality in the United States, via its effects on heart, cerebrovascular and renal disease. Despite its prevalence, the underlying cause(s) of hypertension remain poorly understood. It is clear that there are environmental and hereditary genetic factors that predispose to the development of hypertension; identification of the genetic factors is made difficult, however, by the small effects of many genes coupled with overlying environmental factors. One approach to this problem has been to study single gene disorders that primarily affect blood pressure. The determinants of the molecular bases of glucocorticoid-remediable aldosteronism, Liddle's syndrome, Bartter's syndrome, Gitelman's syndrome and others has done to [sic] much to increase our understanding of renal physiology and the kidneys role in blood pressure regulation. In this project, we describe the discovery of a new form of mendelian hypertension caused by activating mutation in the mineralocorticoid receptor, the effector molecule for aldosterone in the distal nephron. Through characterization of the affected kindred and in vitro analysis of the mutant receptor, we will discern the mechanism by which the mutation activates mineralocorticoid receptor function. It is anticipated that this information will yield insight into normal receptor function, which may prove useful in drug design. By creating a mouse model of the disease, we hope to generate a mechanism to study the effects of a wide variety of steroid agonists and antagonists in vivo, and also to gain insight into the effects of the activated mineralocorticoid receptor in tissues other than the kidney. This project is designed to provide training in molecular and human genetics for the Principal Investigator and to enable him to develop a career in academic Nephrology with a focus on the molecular genetics of hypertension and renal disease.