Adrenal Mineralocorticoid Receptor Activity Regulates Aldosterone and Cortisol Production

项目总结/摘要 了解醛固酮和皮质醇的调节对于更好地理解脑梗死的病理生理学是至关重要的。 心血管疾病这个翻译项目源于新的临床前发现， 以前未知的调节途径醛固酮和皮质醇在肾上腺的水平。具体而言是 肾上腺皮质上的盐皮质激素受体（MR）是MR介导的超短反馈回路的一部分 调节醛固酮产生和调节皮质醇产生的MR介导的抑制途径的一部分。 拟议的F32项目的目标是证明这些调控途径在人类中的存在。 申请人将进行一项3向交叉研究，其中健康受试者将接受所有3种药物 干预，在不同日期随机分配：1）安慰剂，2）MR激动剂（氟氢可的松）和3）MR拮抗剂 （依普利酮）。醛固酮和皮质醇将在直接肾上腺刺激之前和之后用 输注AngII和促肾上腺皮质激素（ACTH）。该项目的目标是： 1)为了验证存在肾上腺MR介导的超短反馈环调节肾上腺皮质激素分泌的假设， 人体内的醛固酮生成。正如临床前模型所证明的那样，在人类中的假设是： 与安慰剂相比，MR激活将减少AngII刺激的醛固酮产生， 与安慰剂相比，MR阻断剂将增加AngII刺激的醛固酮产生。 2)为了验证存在肾上腺MR介导的抑制途径调节皮质醇的假设， 生产正如临床前模型所证明的那样，在人类中的假设是： 与安慰剂相比，MR激活将减少促肾上腺皮质激素刺激的皮质醇产生， MR阻断对促肾上腺皮质激素刺激的皮质醇产生没有影响， 安慰剂 这项研究的结果可以大大提高对醛固酮和皮质醇调节的理解， 并因此成为高血压和心血管疾病的发病机制。培训计划包括专门的 导师Gail Adler，MD，PhD（赞助商），Gordon威廉姆斯，MD（醛固酮专业导师），和 Bernard Rosner博士（生物统计学专业导师），每个人都提供针对申请人需求的专业知识 和目标。此外，申请人将完成临床/翻译研究、临床 试验设计和统计通过严格的两年临床/转化研究学院证书 计划以及专门的课程作业在哈佛T.H.公共卫生学院。这些活动 将为申请人提供必要的工具，对独立职业的发展至关重要 临床/翻译研究员。

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.