MINERALOCORTICOID RECEPTOR PHYSIOLOGY IN HYPERTENSION

描述：(改编自申请人的摘要)人类矿物皮质激素受体(MR)是肾素-血管紧张素-醛固酮途径的最终效应器，也是远端肾单位钠稳态的关键调节器。这些研究人员最近描述了一种由功能突变获得引起的人类孟德尔高血压的新形式。这种新形式的人类孟德尔高血压是由MR的功能突变颗粒引起的。这种突变会导致受体的结构性活性，并改变受体的特异性，如此一来，通常作为MR拮抗剂的孕酮就会发挥激动剂的作用。与妊娠期间孕酮水平的急剧上升一致，该突变的携带者会患上严重的妊娠高血压。以往的研究表明，该突变体通过在螺旋3和螺旋5之间建立一种新的范德华相互作用来实现螺旋3的21-0H独立弯曲。这种螺旋3-螺旋-5相互作用在不同的核受体中高度保守的观察表明，它在受体激活中起着普遍的作用。在这项拨款中，我们建议进行生化和临床研究，以加强我们对MR在人类生理学和高血压方面的作用的了解。他们将评估拟议的MR激活模型，并确定MR特异性和活性所需的特定残基。此外，他们将确定MR活动所需的核协同调节因子，并确定MR激活所需的生化要求。在临床上，他们建议确定在各种临床情况下导致MR突变的疾病的患病率，并最终确定携带该突变的患者中激活的MR对肾脏外的影响。

DESCRIPTION: (Adapted from the applicant's abstract) The human mineralocorticoid receptor (MR) serves as the final effector of the renin-angiotensin-aldosterone pathway and is a key regulator of sodium homeostasis in the distal nephron. These investigators recently described a novel form of human Mendelian hypertension caused by a gain of function mutation novel form of human Mendelian hypertension caused by grain of function mutation in MR. The mutation results in constitutive activity of the receptor and alters receptor specificity such that progesterone, normally an MR antagonist, functions as an agonist. Consistent with the dramatic rise in progesterone levels in pregnancy, carriers of this mutation develop severe pregnancy-related hypertension. Previous studies indicate that bending of helix 3, and that this mutant achieves the 21-0H independent bending of helix 3 via creation of a novel van der Waals interaction between helix 3 and helix 5. The observations that this helix 3- helix-5 interaction is highly conserved among diverse nuclear receptors indicated its general role in receptor activation. In this grant, we propose both biochemical and clinical studies to augment our understanding of MR function in human physiology and hypertension. They will assess the proposed model for MR activation and identify specific residues necessary for MR specificity and activity. Furthermore, they will identify nuclear co-regulators required for MR activity and identify the biochemical requirements for MR activation. Clinically, they propose to determine the prevalence of disease causing MR mutations in a variety of clinical situations and finally, determine extra-renal effects of an activated MR in patients carrying this mutation.