MEMBRANE IMPERMEABLE ALPHA1-ADRENERGIC RECEPTOR

膜不可渗透的 α1 肾上腺素受体

• 批准号: 8360555
• 负责人: Casey D Wright
• 金额: $ 12.31万
• 依托单位: SANFORD RESEARCH/USD
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360555
• 关键词: Admission activity; Adrenergic Antagonists; Adrenergic Receptor; Adverse effects; Antihypertensive Agents; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell membrane; Disease; FDA approved; Funding; G-Protein-Coupled Receptors; Grant; Growth; Heart; Heart failure; Hypertension; Incidence; Individual; Lipids; Membrane; Muscle Tension; Myocardial; Myocardial Infarction; National Center for Research Resources; Nuclear Envelope; Patients; Principal Investigator; Prostate; Prostatic hypertrophy; Receptor Signaling; Research; Research Infrastructure; Resources; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Source; Stress; United States National Institutes of Health; cost; hypertension treatment; indexing; men; postnatal; prevent; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. It is estimated that approximately 9.5 million men over 65 will suffer from benighn prostate hyperplasia (BPH) in 2010, and of these men 87% will suffer hypertension(HTN) and 40% will have a previous admission for heart failure. Although HTN responds positively to alpha1-adrenergic receptor (alpha1-AR) antagonist treatment, the treatment of HTN with alpha1-AR antagonists is at best a third-line option due to an increased incidence of heart failure as highlighted in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). In the heart, alpha1-ARs regulate postnatal growth and myocardial adaptation to stress, and an alpha1A-ERK signaling pathway protects cardiac myocytes from stress. Blockade of alpha1-AR signaling could explain the deleterious effects of alpha1-AR antagonist administration in patients with HTN. In contrast to HTN, BPH is treated effectively with administration of alpha1-AR antagonists and currently several alpha1-AR antagonists are FDA approved for treatment of BPH. This presents a unique circumstance in men where individuals who suffer from both diseases are in a perilous situation where treatment of BPH with an alpha1-AR antagonist can have potentially serious cardiac side effects. Given the common coexistence of HTN and BPH, understanding the interplay of alpha1-ARs in their treatment could have tremendous value in patient treatment options. Recently we demonstrated that alpha1-ARs are expressed on cardiac myocyte nuclear membranes which challenged the long-held dogma that all G-protein coupled receptors (GPCR) localized to the plasma membrane, which is the case for a proportion of alpha1-ARs in prostate smooth muscle cells (SMC). In SMC, a membrane impermeable alpha1-AR antagonist, CGP-12177 (CGP) can inhibit smooth muscle tension whereas this compound, in our preliminary experiments, does not block beneficial alpha1-AR signaling in cardiac myocytes. The overall objective of this research is to determine the localization of alpha1-AR subtypes in prostate and vascular SMCs, how localization impacts signaling, and the efficacy of the membrane impermeable alpha1-AR antagonist CGP in reducing HTN without increasing the indices of heart failure.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 据估计，2010年，约有65岁以上的大约950万男性将患有贝尼前列腺增生（BPH），其中87％的男性将遭受高血压（HTN），而40％的男性将因心力衰竭而接受。尽管HTN对α1-肾上腺素能受体（alpha1-ar）拮抗剂的治疗做出积极反应，但使用alpha1-ar拮抗剂对HTN的治疗充其量是第三次选择，因为心脏衰竭的发生率增加，因为在抗高型和脂肪较低的治疗方面强调了抗型和脂肪较低的治疗，以防止心脏病攻击试验（Allhat）。在心脏中，α1-ARS调节产后生长和对压力的心肌适应，α1A-ERK信号传导途径可保护心肌细胞免受压力。 alpha1-ar信号传导的封锁可以解释α1-ar拮抗剂给药对HTN患者的有害作用。 与HTN相反，BPH通过α1-AR拮抗剂的给药有效治疗，目前已批准了几个α1-AR拮抗剂用于治疗BPH。 在男性中，这是一种独特的情况，在这种情况下，患有两种疾病的个体处于危险情况下，在这种情况下，用alpha1-ar拮抗剂对BPH进行治疗可能会产生严重的心脏副作用。鉴于HTN和BPH的常见共存，了解其治疗中α1-AR的相互作用可能在患者治疗方案中具有巨大的价值。最近，我们证明了α1-ARS在心肌细胞核膜上表达，这挑战了所有G蛋白耦合受体（GPCR）位于质膜的长期以来的教条，这是前列腺平滑肌细胞中Alpha1-ARS的比例。在SMC中，膜不渗透的α1-AR拮抗剂，CGP-12177（CGP）可以抑制平滑肌张力，而在我们的初步实验中，这种化合物不会阻止心肌细胞中有益的α1-AR信号。这项研究的总体目的是确定α1-AR亚型在前列腺和血管SMC中的定位，定位如何影响信号传导以及膜不可渗透的Alpha1-AR拮抗剂CGP在减少HTN中降低HTN的疗效而不增加心力衰竭的组合。