Glucocorticoid Effects on Blood Pressure Regulation

描述(由申请人提供)： 高血压影响着大约20%的美国人，每年约有20万人死于心肌梗死、中风和肾脏疾病，然而，人们对疾病的确切分子原因知之甚少。越来越多的流行病学和实验证据表明，孕妇产前使用糖皮质激素会增加成年后代的血压和心血管疾病。不幸的是，这种效应的确切分子决定因素还不清楚。由于糖皮质激素在不同的组织中引起广泛的发育和生理效应，目前尚不清楚哪种糖皮质激素效应易患高血压。目前，还没有实验方法将糖皮质激素靶向发育中的胎儿特定组织，因此，无法区分初级糖皮质激素的影响和继发性后遗症。 在了解类固醇激素受体功能的精确结构决定因素的研究过程中，我们产生了一种突变的糖皮质激素受体，其对糖皮质激素的敏感性增强。在这项计划中，我们将利用重组小鼠遗传学的最新进展来创造一个功能增强的GR敲入小鼠，这将使我们能够评估糖皮质激素在单个组织中表达的影响，从而深入了解高血压的基本机制。

DESCRIPTION (provided by applicant): Hypertension affects approximately 20% of Americans and is associated with approximately 200,000 deaths annually from myocardial infarction, stroke and renal disease and yet, the precise molecular causes of disease are poorly understood. There is increasing epidemiological and experimental evidence that the prenatal administration of glucocorticoids to pregnant mothers increases blood pressure and cardiovascular disease in adult progeny. Unfortunately, the precise molecular determinants of this effect are not understood. Because glucocorticoids cause a wide range of developmental and physiologic effects in disparate tissues, it is not clear which glucocorticoid effect predisposes to hypertension. There is, at present, no method to experimentally target glucocorticoids to specific tissues in the developing fetus, and thus, distinguishing primary glucocorticoid effects from secondary sequelae has not been possible. In the course of studies to understand precise structural determinants of steroid hormone receptor function, we have generated a mutant glucocorticoid receptor with enhanced sensitivity to glucocorticoids. In this proposal, we will take advantage of recent advances in recombinant mouse genetics to create a gain-of-function GR knock-in mouse, which will allow us to assess the effects of glucocorticoid expression in individual tissues, and thereby gain insight into fundamental mechanisms of hypertension.