Adrenal Mineralocorticoid Receptor Activity Regulates Aldosterone and Cortisol Production

肾上腺盐皮质激素受体活性调节醛固酮和皮质醇的产生

• 批准号: 9760033
• 负责人: Andrea Haas
• 金额: $ 7.42万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-02-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760033
• 关键词: Academy; Acute; Adrenal Cortex; Adrenal Glands; Agonist; Aldosterone; Angiotensin II; Biometry; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Clinical; Clinical Trials Design; Congestive Heart Failure; Corticosterone; Corticotropin; Cosyntropin; Cross-Over Studies; Development; Doctor of Philosophy; Endocrinology; Feedback; Fludrocortisone; Functional disorder; Future; Glucocorticoids; Goals; Heart; Human; Hydrocortisone; Hypertension; Incubated; Individual; Infusion procedures; Intervention; Investigation; Knowledge; Lead; Measures; Mediating; Mentors; Mentorship; Mineralocorticoid Receptor; Mineralocorticoids; Obesity; Participant; Pathogenesis; Pathway interactions; Patients; Physiological; Placebos; Population; Potassium; Pre-Clinical Model; Process; Production; Public Health Schools; Randomized; Rattus; Receptor Activation; Regulation; Regulatory Pathway; Research; Research Project Grants; Site; Testing; Time; Tissues; Training; Translational Research; United States; Zona Fasciculata; Zona Glomerulosa; career; certificate program; eplerenone; improved; insight; medical specialties; mortality; novel; patient oriented research; pre-clinical; statistics; stem; tool; translational scientist

PROJECT SUMMARY/ABSTRACT Understanding aldosterone and cortisol regulation is essential for better understanding the pathophysiology of cardiovascular disease. This translational project stems from novel preclinical findings demonstrating a previously unknown regulatory pathway for aldosterone and cortisol at the level of the adrenal. Specifically, the mineralocorticoid receptor (MR) present on the adrenal cortex is part of a MR-mediated ultra-short feedback loop regulating aldosterone production and part of a MR-mediated inhibitory pathway regulating cortisol production. The goal of the proposed F32 project is to demonstrate the existence of these regulatory pathways in humans. The applicant will perform a 3-way cross-over study in which healthy participants will receive all three interventions, randomized on separate days: 1) placebo, 2) MR agonist (fludrocortisone), and 3) MR antagonist (eplerenone). Aldosterone and cortisol will be measured before and after direct adrenal stimulation with an infusion of AngII and cosyntropin (ACTH). The aims of the project are: 1) To test the hypothesis that there is an adrenal MR-mediated ultra-short feedback loop regulating aldosterone production in humans. As demonstrated in a preclinical model, the hypothesis in humans is: MR activation will decrease AngII-stimulated aldosterone production compared to placebo AND MR blockade will increase AngII-stimulated aldosterone production compared to placebo. 2) To test the hypothesis that there is an adrenal MR-mediated inhibitory pathway regulating cortisol production. As demonstrated in a preclinical model, the hypothesis in humans is: MR activation will decrease cosyntropin-stimulated cortisol production compared to placebo AND MR blockade will have no effect on cosyntropin-stimulated cortisol production compared to placebo. The results of the proposed research could greatly enhance understanding of aldosterone and cortisol regulation, and thus the pathogenesis of hypertension and cardiovascular disease. The training plan includes dedicated mentorship by Gail Adler, MD, PhD (sponsor), Gordon Williams, MD (specialty mentor in aldosterone), and Bernard Rosner, PhD (specialty mentor in biostatistics), each offering expertise tailored to the applicant’s needs and goals. Additionally, the applicant will complete formal training in clinical/translational investigation, clinical trial design, and statistics through a rigorous two-year Clinical/Translational Research Academy Certificate Program as well as dedicated coursework at the Harvard T.H. Chan School of Public Health. These activities will provide the applicant with the necessary tools critical for development toward a career as an independent clinical/translational researcher.

项目摘要/摘要 了解醛固酮和皮质醇调节对于更好地理解的病理生理至关重要 心血管疾病。这个翻译的项目步骤从新颖的临床前发现证明了一个 以前未知的醛固酮和皮质醇在肾上腺水平的调节途径。具体来说， 肾上腺皮质上存在的矿物皮质激素受体（MR）是MR介导的超短声反馈环的一部分 调节醛固酮的产生和MR介导的控制皮质醇产生的抑制途径的一部分。 拟议的F32项目的目的是证明人类中这些监管途径的存在。 申请人将进行三路交叉研究，健康参与者将接受这三个 干预措施，在单独的日内随机：1）安慰剂，2）MR Agonist（Fludrocortisone）和3）MR拮抗剂 （eplerenone）。醛固酮和皮质醇将在直接肾上腺刺激之前和之后测量 输注Angii和Cosyntropin（ACTH）。该项目的目的是： 1）检验假设有肾上腺MR介导的超短反馈环调节的假设 人类的醛固酮产量。正如临床前模型所证明的那样，人类的假设是： 与安慰剂和安慰剂相比 与安慰剂相比，MR Blockade将增加Angii刺激的醛固酮产量。 2）测试假设有肾上腺MR介导的抑制途径来调节皮质醇 生产。正如临床前模型所证明的那样，人类的假设是： 与安慰剂和安慰剂和 MR Blockade对cosyntropin刺激的皮质醇的产生没有影响 安慰剂。 拟议研究的结果可以大大增强对醛固酮和皮质醇调节的理解， 因此，高血压和心血管疾病的发病机理。培训计划包括专用 盖尔·阿德勒（Gail Adler）医学博士（赞助商），医学博士（赞助商）的指导 伯纳德·罗斯纳（Bernard Rosner），博士学位（生物统计学专业指导者），每个提供满足申请人需求的专家 和目标。此外，申请人将完成临床/翻译调查的正式培训 试验设计和通过严格的两年临床/转化研究学院证书进行的统计数据 计划以及哈佛大学的专门课程工作陈公共卫生学院。这些活动 将为申请人提供必要的工具，以发展为独立的职业至关重要 临床/翻译研究人员。