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

基本信息

批准号：
10222165
负责人：
Joshua J Joseph
金额：
$ 5.35万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10222165
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

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

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项目摘要

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.

项目摘要/摘要医学博士Joshua J. Joseph是俄亥俄州立大学的内分泌学，糖尿病和代谢。约瑟夫博士寻求一个受过指导的患者 - 面向研究职业发展奖，以获取技能，知识和考虑研究经验对于2型糖尿病领域的临床科学家而言至关重要（T2DM）预防。该建议旨在确定肾素 - 血管紧张素 - 醛固酮系统的作用（RAAS）在葡萄糖代谢和非裔美国人（AAS）中T2DM的发展中。 AAS是1.7 在美国开发T2DM的时间和非西班牙裔的可能死于T2DM的可能性是T2DM的两倍白人。这是一个迫切需要的领域。该提案的目标是确定角色 RAAS，内皮蛋白-1，ARMC5（Armadillo重复5）和葡萄糖中的RAAS拮抗作用代谢和糖尿病的发展。该研究建议的具体目的是：（1）确定醛固酮和内皮素-1的关联，单独并与HOMA-胰岛素抵抗相结合， HOMA-β细胞功能，禁食等离子体葡萄糖和入射T2DM在没有T2DM的AAS中的基线时T2DM 杰克逊心脏研究（JHS）；（2）确定a）预测损坏的横截面关联血浆醛固酮，血浆肾素活性，禁食葡萄糖和普遍的T2DM和B）的ARMC5突变 JHS中AAS中与T2DM事件的纵向关联；（3）确定RAAS的影响拮抗剂或王朝和Neprilysin拮抗与安慰剂，葡萄糖代谢的变化超过6 通过AAS中的葡萄糖夹研究评估的几个月。对于AIM 1，我们提出了预测流行病学 JHS的分析是对AAS中心血管疾病的观察性研究，以确定醛固酮和内皮素-1的组合与葡萄糖代谢，普遍和入射的关联 T2DM。对于AIM 2，我们建议在JHS中进行遗传分析，以确定ARMC5遗传的关联具有葡萄糖代谢，普遍和入射T2DM成分的变体。对于AIM 3，我们提出了26- 周临床试验，以测试RAAS拮抗作用对AAS中β细胞功能和胰岛素抵抗的影响葡萄糖耐受性受损。奖励期内的目标包括开发设计专业知识，通过指导的研究，教学课程，临床研究的绩效，分析和介绍，以及葡萄糖代谢，临床试验方法，遗传，基因组临床研究的正式培训以及其他 - 组分析技术和预测/因果建模。长期职业目标包括发展为独立研究者的职业，专注于寻找预防和治疗T2DM，特别是在历史上了解生物医学研究中的人群中。提议研究旨在为RAAS对葡萄糖代谢变化的贡献提供新的见解 T2DM的发展。这项工作将奠定基础，以开发针对T2DM的新型治疗靶标。