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

肾素-血管紧张素-醛固酮系统、ARMC5 和脑啡肽酶在非裔美国人葡萄糖代谢中的作用

• 批准号: 10171839
• 负责人: Joshua J Joseph
• 金额: $ 18.71万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171839
• 关键词: Address; Adrenal Cortex; African American; Aldosterone; Angiotensin Receptor; Area; Armadillo Repeat; Award; Beta Cell; Biomedical Research; Blood Pressure; CYP11B2 gene; Cardiovascular Diseases; Cell physiology; Clinical Research; Clinical Trials; Closure by clamp; Development; Diabetes Mellitus; Diabetes prevention; Dose; Endocrinology; Endothelin-1; Epidemiology; European; Foundations; Functional disorder; Future; Gene Mutation; Genetic; Genomics; Glucose Clamp; Goals; Health; High Prevalence; Hormonal; Hormones; Hyperaldosteronism; Hyperglycemia; Hypertension; Incidence; Individual; Insulin Resistance; Intervention; Investigation; Jackson Heart Study; Knowledge; Mentored Patient-Oriented Research Career Development Award; Mentors; Metabolism; Methodology; Mutation; Neprilysin; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Ohio; Pathway interactions; Patients; Performance; Placebos; Plasma; Play; Population; Practice Guidelines; Prediabetes syndrome; Prevalence; Prevention; Prevention trial; Primary Hyperaldosteronism; Public Health; Regulation; Renin; Renin-Angiotensin-Aldosterone System; Research; Research Personnel; Research Proposals; Risk; Risk Factors; Role; Scientist; Skeletal Muscle; Sodium; System; Techniques; Testing; Therapeutic; Time; Training; Translating; Tumor Suppressor Genes; United States; Universities; Variant; Vasoconstrictor Agents; Woman; Work; blood pressure regulation; career; causal model; clinical investigation; design; experience; fasting glucose; fasting plasma glucose; genetic analysis; genetic variant; glucose metabolism; glucose uptake; health disparity; high risk; impaired glucose tolerance; improved; inhibitor/antagonist; insight; lifetime risk; mortality; new therapeutic target; novel; novel strategies; prevent; professor; racial and ethnic disparities; skills; valsartan

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.

项目概要/摘要 Joshua J. Joseph，医学博士，是该部门的助理教授 俄亥俄州立大学内分泌学、糖尿病和代谢学博士约瑟夫正在寻找一位指导患者。 定向研究职业发展奖，以获得技能、知识和指导 研究经验对于 2 型糖尿病领域的临床科学家职业至关重要 该提案旨在确定肾素-血管紧张素-醛固酮系统的作用。 非裔美国人 (AA) 中葡萄糖代谢和 T2DM 发展的 (RAAS) 为 1.7。 与非西班牙裔人相比，美国人患 T2DM 的可能性是非西班牙裔人的 1 倍，死于 T2DM 的可能性是非西班牙裔人的两倍 因此，这代表了一个迫切需要的领域，该提案的目标是确定角色。 RAAS、内皮素-1、ARMC5（含有 5 的犰狳重复序列）和葡萄糖中的 RAAS 拮抗作用 本研究提案的具体目标是：（1）确定。 醛固酮和内皮素-1（单独或组合）与 HOMA 胰岛素抵抗的关联， 基线时无 T2DM 的 AA 中的 HOMA-β 细胞功能、空腹血糖和 T2DM 发病率 杰克逊心脏研究 (JHS)；(2) 确定 a) 预测损伤的横截面关联 ARMC5 突变与血浆醛固酮、血浆肾素活性、空腹血糖和流行的 T2DM 相关，b) JHS 中 AA 与 T2DM 事件的纵向关联 (3) 以确定 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 通过 AA 中的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（一项关于 AA 中心血管疾病的观察性调查）中的分析，以确定 醛固酮和内皮素-1 的组合与葡萄糖代谢、流行和事件的关联 对于目标 2，我们建议在 JHS 中进行遗传分析，以确定 ARMC5 遗传的关联。 对于目标 3，我们提出了 26- 具有葡萄糖代谢成分的变异体、流行的和偶发的 T2DM。 为期一周的临床试验，测试 RAAS 拮抗剂对 AA 中 β 细胞功能和胰岛素抵抗的影响 奖励期间的目标包括开发设计方面的专业知识， 通过指导研究、教学课程作业进行临床研究的表现、分析和展示， 以及葡萄糖代谢临床研究、临床试验方法、遗传学、基因组方面的正式培训 其他组学分析技术和预测/因果建模包括长期职业目标。 发展作为一名独立调查员的职业生涯，专注于寻找预防和预防新方法 治疗 T2DM，特别是生物医学研究中历史上未充分研究的人群。 研究旨在为 RAAS 对葡萄糖代谢变化的贡献提供新的见解 这项工作将为开发 T2DM 的新治疗靶点奠定基础。