MINERALOCORTICOID RECEPTOR PHYSIOLOGY IN HYPERTENSION

产品说明：（改编自申请人的摘要）人盐皮质激素受体（MR）作为肾素-血管紧张素-醛固酮途径的最终效应物，是远端肾单位钠稳态的关键调节因子。这些研究人员最近描述了一种新的形式的人类孟德尔高血压引起的功能突变的获得的新形式的人类孟德尔高血压引起的颗粒的功能突变的MR。突变的结果在组成活动的受体和改变受体的特异性，如孕酮，通常是一种MR拮抗剂，作为激动剂的功能。与妊娠期孕酮水平的急剧上升相一致，这种突变的携带者发展为严重的妊娠相关高血压。先前的研究表明，螺旋3的弯曲，并且该突变体通过在螺旋3和螺旋5之间产生新的货车德瓦尔斯相互作用来实现螺旋3的21-OH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结果表明其在受体活化中的一般作用。在这项资助中，我们提出了生物化学和临床研究，以增加我们对人类生理学和高血压中MR功能的理解。他们将评估MR激活的拟议模型，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活性所需的核辅调节因子，并确定MR激活的生化要求。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的肾外效应。

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.