GENETIC STUDIES OF MINERALOCORTICOID FUNCTION

描述（改编自应用程序） 高血压是美国最常见的疾病之一， 20%的人口。它也是发病的主要原因之一， 死亡率在美国，通过其对心脏，脑血管和 肾脏疾病尽管高血压患病率很高， 仍然知之甚少。很明显，环境和 易患高血压的遗传因素; 然而，遗传因素的识别是困难的，因为小的 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是研究单基因疾病， 影响血压。分子基础的决定因素 糖皮质激素可治疗的醛固酮增多症，利德尔综合征，巴特综合征， Gitelman综合征和其他人已经做了[原文如此]很多，以增加我们的 了解肾脏生理学和肾脏在血压中的作用 调控在这个项目中，我们描述了一种新形式的发现， 盐皮质激素激活突变引起的孟德尔式高血压 受体，远端肾单位中醛固酮的效应分子。通过 受影响亲属的表征和突变体的体外分析 受体，我们将辨别突变激活的机制， 盐皮质激素受体功能预计这些信息 将有助于了解正常的受体功能，这可能有助于 药物设计通过建立这种疾病的小鼠模型，我们希望产生一种 研究各种类固醇激动剂的作用机制， 拮抗剂在体内，并获得深入了解的影响，激活 盐皮质激素受体在肾脏以外的组织。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 研究者，使他能够发展学术肾脏病学的职业生涯， 重点研究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.