Adrenal Mineralocorticoid Receptor Activity Regulates Aldosterone and Cortisol Production

项目摘要/摘要 了解醛固酮和皮质醇的调节对于更好地了解高血压的病理生理机制是至关重要的。 心血管疾病。这一翻译项目源于新的临床前发现，证明了 先前未知的醛固酮和皮质醇在肾上腺水平的调节途径。具体地说， 肾上腺皮质上的盐皮质激素受体(Mr)是mr介导的超短反馈环的一部分。 调节醛固酮的产生和MR介导的调节皮质醇产生的抑制通路的一部分。 拟议的F32项目的目标是证明这些调节通路在人类中的存在。 申请者将进行三方交叉研究，健康参与者将获得所有三项 干预措施，在不同的日期随机进行：1)安慰剂，2)MR激动剂(氟可的松)，3)MR拮抗剂 (依普利酮)。测定肾上腺直接刺激前后的醛固酮和皮质醇。 血管紧张素转换酶和促肾上腺皮质激素(ACTH)。该项目的目标是： 1)检验存在肾上腺MR介导的超短反馈环调节的假设 人体产生的醛固酮。正如临床前模型所展示的那样，人类的假设是： 与安慰剂和安慰剂相比，MR激活将减少Angii刺激的醛固酮的产生 与安慰剂相比，布洛克先生将增加血管紧张素转换酶刺激的醛固酮的产量。 2)检验存在肾上腺MR介导的抑制通路调节皮质醇的假设 制作。正如临床前模型所展示的那样，人类的假设是： 与安慰剂和安慰剂相比，MR激活将减少COS刺激的皮质醇产生 MR阻滞剂对促肾上腺皮质激素刺激的皮质醇的产生没有影响 安慰剂。 拟议的研究结果可以极大地提高对醛固酮和皮质醇调节的理解， 从而导致高血压和心血管疾病的发生。培训计划包括专门的 Gail Adler医学博士(赞助商)、Gordon Williams医学博士(醛固酮专业导师)的指导 伯纳德·罗斯纳博士(生物统计学专业导师)，每个人都提供根据申请者需求量身定做的专业知识 和目标。此外，申请者还将完成临床/转化性研究、临床 通过严格的两年制临床/转化研究学院证书进行试验设计和统计 项目以及哈佛大学公共卫生学院的专业课程。这些活动 将为申请者提供必要的工具，这些工具对于独立职业发展至关重要 临床/翻译研究人员。

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.