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

项目摘要/摘要 约书亚·J·约瑟夫，医学博士，助理教授 俄亥俄州立大学内分泌学、糖尿病和新陈代谢。约瑟夫医生正在寻找一位有指导的病人- 以研究为导向的职业发展奖，以获得技能、知识和指导 作为2型糖尿病领域的临床科学家的职业生涯所必需的研究经验 (2)预防2型糖尿病。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)中的糖代谢和T2 DM的发生。AAS为1.7 在美国患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 白色的。因此，这是一个迫切需要的领域。这项提案的目标是确定 RAAS在葡萄糖中的拮抗作用：内皮素-1、ARMC5(含5个螳螂重复序列) 代谢与糖尿病的发展。本研究方案的具体目的是：(1)确定 醛固酮和内皮素-1单独和联合与胰岛素抵抗的关系 基线时无T2 DM的AA患者的HOMA-β细胞功能、空腹血糖和T2 DM发生率 杰克逊心脏研究(JHS)；(2)确定a)预测损伤的横断面关联 ARMC5突变与血浆醛固酮、血浆肾素活性、空腹血糖、T2 DM和b的流行 JHS中AAS与T2 DM发病的纵向关联；(3)确定RAAS的影响 糖代谢改变超过6的拮抗剂或RAAS和neprilysin拮抗剂与安慰剂的比较 通过对AAs进行葡萄糖钳夹试验评估月数。对于目标1，我们提出了预测性流行病学 在JHS中进行的分析，这是一项关于AA心血管疾病的观察性调查，以确定 醛固酮和内皮素-1的组合与糖代谢、流行和偶发的关系 T2 DM。对于目标2，我们建议在JHS中进行遗传分析，以确定ARMC5基因与 具有糖代谢成分的变异，流行和发病的T2 DM。对于目标3，我们建议26- RAS拮抗剂对AAS患者β细胞功能及胰岛素抵抗影响的周临床试验 糖耐量受损。获奖期间的目标包括开发设计方面的专业知识， 通过指导性研究、教学课程、 接受过葡萄糖代谢临床研究、临床试验方法学、遗传学、基因组学方面的正规培训 以及其他经济学分析技术和预测/因果建模。长期的职业目标包括 发展作为一名独立调查员的职业生涯，专注于寻找预防和 治疗2型糖尿病，特别是在生物医学研究中历史上研究不足的人群中。建议数 研究旨在为RAAS在糖尿病糖代谢变化中的作用提供新的见解 2型糖尿病的发展。这项工作将为开发新的T2 DM治疗靶点奠定基础。

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.