MINERALOCORTICOID RECEPTOR PHYSIOLOGY IN HYPERTENSION

描述：（改编自申请人摘要）人矿化皮质激素受体（MR）是肾素-血管紧张素-醛固酮通路的最终效应器，是远端肾单位钠稳态的关键调节剂。这些研究人员最近描述了一种由MR中功能突变颗粒引起的新型人类孟德尔高血压，这种突变导致受体的组成活性和受体特异性改变，从而使通常作为MR拮抗剂的黄体酮发挥激动剂的作用。与妊娠期黄体酮水平的急剧上升相一致，这种突变的携带者会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之间建立新的范德华相互作用来实现螺旋3的21-0H独立弯曲。观察到这种螺旋3-螺旋5相互作用在不同的核受体中高度保守，表明它在受体激活中的一般作用。在这项资助中，我们建议进行生化和临床研究，以增强我们对MR在人体生理学和高血压中的功能的理解。他们将评估提议的MR激活模型，并确定MR特异性和活性所需的特定残基。此外，他们将确定核磁共振活性所需的核共调节因子，并确定核磁共振激活的生化要求。在临床上，他们建议确定在各种临床情况下引起MR突变的疾病的患病率，并最终确定携带该突变的激活MR患者的肾外效应。

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.