Vascular Interactions of Estrogen Receptor GPR30 and the Renin-Angiotensin System

雌激素受体 GPR30 和肾素-血管紧张素系统的血管相互作用

• 批准号: 8111440
• 负责人: Sarah H. Lindsey
• 金额: $ 9.72万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111440
• 关键词: Acute; Address; Agonist; American Heart Association; Angiotensin II; Animals; Area; Award; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Culture System; Cell Culture Techniques; Chronic; Clinical; Collaborations; Commit; Communities; Core Facility; Data; Development; Diet; Dose; Educational process of instructing; Endothelium; Ensure; Environment; Equipment; Estrogen Nuclear Receptor; Estrogen Receptors; Estrogens; Extracellular Matrix Proteins; Fellowship; Female; Financial Support; Functional disorder; Funding; Future; G-Protein-Coupled Receptors; Gender; Gene Expression; Genes; Genomics; Goals; Growth Factor Receptors; Growth Hormone Receptor; Hormone replacement therapy; Hormones; Hypertension; In Vitro; Incidence; Institutes; Laboratories; Mediating; Menopause; Mentors; Mesentery; Modeling; Phase; Postmenopause; Premenopause; Preparation; Publications; Rattus; Regulation; Relaxation; Renin-Angiotensin System; Research; Research Personnel; Resistance; Resources; Rodent Model; Role; Secure; Smooth Muscle Myocytes; Sodium Chloride; Steroids; Techniques; Thinking; Training; United States National Institutes of Health; Universities; Vascular Smooth Muscle; Vasodilation; Woman; Work; career; clinically relevant; congenic; feeding; forest; in vivo; kidney vascular structure; male; novel; planetary Atmosphere; pressure; programs; protective effect; receptor; response; salt sensitive; scientific organization; skills; success; vasoconstriction

DESCRIPTION (provided by applicant): My career goal is to secure independent NIH funding and establish a successful research program elucidating the role of the GPR30 receptor in the cardiovascular effects of estrogen. My potential to become an independent investigator not only includes scientific drive and success, evidenced by an American Heart Association postdoctoral fellowship, but also commitment to the scientific community, indicated by my work in scientific organizations such as ASPET. This transition award will allow me to acquire the additional techniques and critical thinking skills necessary for success as an independent investigator. The Hypertension and Vascular Research Center at Wake Forest University presents an optimal environment for this training due to the numerous resources available and the collegial atmosphere. These resources include not only scientific equipment and core facilities but also opportunities for teaching, interdepartmental collaboration, and professional development. My mentor, Dr. Mark Chappell, has an excellent funding record, an extensive publication record, and is well-respected among the scientific community. His excellent mentoring skills will ensure my success as an independent investigator. Premenopausal females have a lower incidence of many cardiovascular diseases, including hypertension. Because this protection steeply declines after menopause, we know that estrogen is at least partially responsible for these beneficial effects. There are two known estrogen receptor subtypes that mediate the genomic actions of this hormone; however, it is not known whether the newly discovered G-protein coupled receptor 30 (GPR30) contributes to estrogen's cardiovascular effects. Our laboratory utilizes the mRen2.Lewis rat, a unique angiotensin II-dependent, estrogen-sensitive, and salt-sensitive hypertensive model which appropriately reflects the higher blood pressure and salt-sensitivity seen in postmenopausal women. Our previous data show that in vivo administration of the selective GPR30 agonist G-1 in ovariectomized females significantly reduces blood pressure, alters vascular gene expression of renin-angiotensin system components, and reduces angiotensin II-induced vasoconstriction. These results suggest that GPR30 counteracts an activated renin-angiotensin system. G-1 also induces endothelium-independent vasorelaxation, suggesting receptor localization in vascular smooth muscle. We hypothesize that GPR30 exerts beneficial cardiovascular effects by opposing the actions of Ang II in vascular smooth muscle cells. Separating the actions of estrogen at GPR30 from those mediated by its nuclear estrogen receptors may elucidate the current controversy surrounding hormone replacement therapy. The proposal will take a comprehensive approach utilizing an in vitro cell culture system, an ex vivo isolated resistance vessel preparation, and in vivo analysis of the congenic mRen2.Lewis hypertensive animal. During the mentored year, I will determine whether GPR30 activation in mesenteric smooth muscle cells disrupts the response to angiotensin II by altering Ca2+ storage. For the independent phase, I have outlined three aims: (1) establish whether gender and estrogen status regulate vascular GPR30 and RAS component expression in the mRen2 strain.; (2) determine whether GPR30 activation in vascular smooth muscle cells alters the expression of renin-angiotensin system components and their associated functions; and (3) Assess whether high salt alters vascular GPR30 expression and whether G-1 ameliorates salt-sensitivity by altering renovascular function. These studies will establish the regulation of vascular GPR30 expression and assess its acute and chronic interaction with the renin-angiotensin system. This transition award will provide me the additional mentoring necessary to achieve future success as an independent investigator and will allow me to study a novel area of research which is clinically relevant. Information on the role of GPR30 in the cardiovascular effects of estrogen may alleviate the current controversy on hormone replacement in postmenopausal women. I am committed to maintaining financial support from institutes such as the NIH in order to sustain an independent laboratory and make significant contributions to the scientific community. PUBLIC HEALTH RELEVANCE: Premenopausal females have a lower incidence of many cardiovascular diseases, including hypertension. Because this protection steeply declines after menopause, we know that estrogen has beneficial effects. There are two known estrogen receptors that mediate the long-term actions of this hormone; however, it is not known whether the newly discovered G-protein coupled receptor 30 (GPR30) contributes to estrogen's protective effects. Information on the role of GPR30 in the beneficial effects of estrogen may alleviate the current controversy on hormone replacement in postmenopausal women.

描述（由申请人提供）：我的职业目标是确保独立的NIH资金并建立成功的研究计划，以阐明GPR30受体在雌激素心血管效应中的作用。我成为独立研究者的潜力不仅包括科学驱动力和成功，这是美国心脏协会博士后奖学金所证明的，而且还对科学界的承诺也证明了我在ASPET等科学组织中的工作表明。该过渡奖将使我能够获得作为独立研究者成功所需的其他技术和批判性思维技能。 Wake Forest University的高血压和血管研究中心为这项培训提供了一个最佳的环境，这是由于可用的众多资源和大学氛围。这些资源不仅包括科学设备和核心设施，还包括教学，部门间协作和专业发展的机会。我的导师马克·查佩尔（Mark Chappell）博士拥有出色的资金记录，广泛的出版物记录，并且在科学界得到了很好的尊重。他出色的指导能力将确保我作为独立调查员的成功。绝经前女性的许多心血管疾病的发生率较低，包括高血压。因为这种保护在更年期后急剧下降，所以我们知道雌激素至少对这些有益效果负有部分责任。有两种已知的雌激素受体亚型介导这种激素的基因组作用。但是，尚不清楚新发现的G蛋白偶联受体30（GPR30）是否有助于雌激素的心血管效应。我们的实验室利用Mren2.Lewis大鼠，这是一种独特的血管紧张素II II依赖性，对雌激素敏感和盐敏感的高血压模型，可适当反映绝经后女性的血压和盐敏感性较高。我们先前的数据表明，在卵巢切除的女性中，体内给药可显着降低血压，改变肾素 - 血管紧张素系统成分的血管基因表达，并减少血管紧张素II诱导的血管诱导的血管收缩。这些结果表明GPR30抵消了激活的肾素 - 血管紧张素系统。 G-1还诱导内皮依赖性的血管延缓，表明受体定位在血管平滑肌中。我们假设GPR30通过反对ANG II在血管平滑肌细胞中的作用来发挥有益的心血管效应。将GPR30处雌激素的作用与由其核雌激素受体介导的作用分开可能阐明围绕激素替代疗法的当前争议。该提案将利用体外细胞培养系统，实体分离的抗药性血管制备以及对Encenic Mren2.Lewis高血压动物的体内分析采用全面的方法。在指导年份，我将确定肠系膜平滑肌细胞中的GPR30激活是否通过改变Ca2+储存来破坏对血管紧张素II的反应。对于独立阶段，我概述了三个目的：（1）确定性别和雌激素状态是否调节MREN2菌株中的血管GPR30和RAS成分表达。 （2）确定血管平滑肌细胞中的GPR30激活是否改变了肾素 - 血管紧张素系统成分及其相关功能的表达； （3）评估高盐是否改变了血管GPR30表达以及G-1是否通过改变肾血管功能来缓解盐的敏感性。这些研究将确定血管GPR30表达的调节，并评估其与肾素 - 血管紧张素系统的急性和慢性相互作用。该过渡奖将为我提供作为独立研究者未来成功所必需的额外指导，并使我能够研究一个在临床上相关的新研究领域。有关GPR30在雌激素心血管效应中的作用的信息可能会减轻绝经后妇女激素替代的当前争议。我致力于维持NIH等机构的财政支持，以维持独立的实验室并为科学界做出重大贡献。 公共卫生相关性：绝经前女性的许多心血管疾病的发病率较低，包括高血压。因为这种保护在更年期后急剧下降，所以我们知道雌激素具有有益的作用。有两个已知的雌激素受体介导这种激素的长期作用。但是，尚不清楚新发现的G蛋白偶联受体30（GPR30）是否有助于雌激素的保护作用。有关GPR30在雌激素有益作用中作用的信息可能会减轻绝经后妇女激素替代的当前争议。