The Role of The Renin-Angiotensin-Aldosterone System, ARMC5, and Neprilysin in Glucose Metabolism among African Americans

项目概要/摘要 约书亚J.约瑟夫，医学博士，是一个助理教授在司 俄亥俄州州立大学内分泌学、糖尿病和代谢学。约瑟夫医生寻求一个指导病人- 定向研究职业发展奖，以获得技能，知识，并指导 研究经验，是必不可少的职业生涯作为一个临床科学家在2型糖尿病领域 （T2 DM）预防。这项建议旨在确定肾素-血管紧张素-醛固酮系统的作用 （RAAS）在非裔美国人（AAs）中葡萄糖代谢和T2 DM发展中的作用。A = 1.7 在美国发生T2 DM的可能性是非西班牙裔的两倍，死于T2 DM的可能性是非西班牙裔的两倍。 白人因此，这是一个迫切需要的领域。本提案的目的是确定 RAAS、内皮素-1、ARMC 5（含有5个重复序列的犰狳）和RAAS拮抗作用在葡萄糖 代谢和糖尿病的发展。本研究建议的具体目标是：（1）确定 醛固酮和内皮素-1单独和联合与HOMA-胰岛素抵抗的关系， 在基线时无T2 DM的AA中，HOMA-β细胞功能、空腹血糖和T2 DM事件 杰克逊心脏研究（JHS）;（2）确定a）预测的损害性心脏病的横截面相关性， ARMC 5突变与血浆醛固酮、血浆肾素活性、空腹血糖和T2 DM患病率的关系以及B） JHS中AA与T2 DM事件的纵向关联;（3）确定RAAS的影响 拮抗作用或RAAS和脑啡肽酶拮抗作用与安慰剂相比，葡萄糖代谢变化超过6 在AA中通过葡萄糖钳夹研究评估的月数。对于目标1，我们提出预测流行病学 JHS中的分析，这是一项对AA中心血管疾病的观察性研究， 醛固酮和内皮素-1联合与糖代谢的关系 2型糖尿病。对于目标2，我们建议在JHS中进行遗传分析，以确定ARMC 5遗传相关性。 具有葡萄糖代谢组分的变体，流行和偶发T2 DM。对于目标3，我们建议26- 一项为期一周的临床试验，以测试RAAS拮抗作用对患有以下疾病的AA中β细胞功能和胰岛素抵抗的影响： 葡萄糖耐量受损授予期间的目标包括开发设计方面的专业知识， 通过指导研究，教学课程， 并接受过葡萄糖代谢临床研究、临床试验方法学、遗传学、基因组学方面的正式培训 以及其他组学分析技术和预测/因果建模。长期职业目标包括 作为一名独立调查员，致力于寻找预防和治疗癌症的新方法， 治疗T2 DM，特别是在生物医学研究中历史上未充分研究的人群中。拟议 这项研究旨在为RAAS对葡萄糖代谢变化的贡献提供新的见解， T2 DM的发展。本研究为开发T2 DM治疗新靶点奠定了基础。

PROJECT SUMMARY/ABSTRACT Joshua J. Joseph, MD, is an Assistant Professor in the Division of Endocrinology, Diabetes and Metabolism at The Ohio State University. Dr. Joseph seeks a Mentored Patient- Oriented Research Career Development Award in order to obtain the skills, knowledge, and mentored research experience that are essential for a career as a clinician scientist in the field of type 2 diabetes mellitus (T2DM) prevention. This proposal is aimed at determining the role of the renin-angiotensin-aldosterone system (RAAS) in glucose metabolism and the development of T2DM among African Americans (AAs). AAs are 1.7 times as likely to develop T2DM in the US and are twice as likely to die from T2DM compared to non-Hispanic whites. Thus, this represents an area of critical need. The objectives of this proposal are to determine the role of the RAAS, endothelin-1, ARMC5 (armadillo repeat containing 5) and RAAS antagonism in glucose metabolism and the development of diabetes. The specific aims of this research proposal are: (1) to determine the associations of aldosterone and endothelin-1, individually and combined, with HOMA-insulin resistance, HOMA-β cell function, fasting plasma glucose and incident T2DM among AAs without T2DM at baseline in the Jackson Heart Study (JHS); (2) to determine a) the cross-sectional associations of predicted damaging ARMC5 mutations with plasma aldosterone, plasma renin activity, fasting glucose, and prevalent T2DM and b) the longitudinal association with incident T2DM among AAs in the JHS; (3) to determine the impact of RAAS antagonism or RAAS and neprilysin antagonism vs. placebo with changes in glucose metabolism over 6 months assessed via glucose clamp studies among AAs. For Aim 1, we propose predictive epidemiological analyses in the JHS, an observational investigation of cardiovascular disease among AAs, to determine the association of a combination of aldosterone and endothelin-1 with glucose metabolism, prevalent and incident T2DM. For Aim 2, we propose genetic analyses in the JHS, to determine the association of ARMC5 genetic variants with components of glucose metabolism, prevalent and incident T2DM. For Aim 3, we propose a 26- week clinical trial to test the effect of RAAS antagonism on β-cell function and insulin resistance in AAs with impaired glucose tolerance. The goals during the award period include developing expertise in the design, performance, analysis and presentation of clinical research through mentored research, didactic coursework, and formal training in clinical investigation of glucose metabolism, clinical trial methodology, genetic, genomic and other –omic analytic techniques and predictive/causal modeling. Long-term career goals include developing a career as an independent investigator focused on finding new approaches for preventing and treating T2DM, particularly among historically understudied populations in biomedical research. The proposed research aims to provide new insights into the contribution of the RAAS to changes in glucose metabolism in the development of T2DM. This work will lay the foundation to develop novel therapeutic targets for T2DM.