Development of a Metabolite Signature of Metformin Prevention for Type 2 Diabetes

二甲双胍预防 2 型糖尿病的代谢特征的开发

• 批准号: 8917206
• 负责人: Geoffrey A. Walford
• 金额: $ 14.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-26 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8917206
• 关键词: Acute; Adult; Amputation; Arts; Award; Biochemical; Biological; Blindness; Branched-Chain Amino Acids; Characteristics; Chronic; Chronic Kidney Failure; Clinical; Clinical Medicine; Clinical Sciences; Clinical Trials; Development; Development Plans; Diabetes Mellitus; Diabetes prevention; Elements; Endocrinology; Environment; Epidemic; Foundations; Funding; General Hospitals; Genetic; Genetic Research; Genomics; Genotype; Glipizide; Glucose; Goals; Health; Heart; Heart Diseases; Hospitals; Human; Human Genetics; Incidence; Individual; Institutes; Internal Medicine; Intervention; Lead; Massachusetts; Medical Genetics; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolic Pathway; Metformin; Methods; Mission; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Pathway interactions; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Physicians; Physiology; Prevention; Prevention strategy; Preventive Intervention; Process; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Scientist; Source; Stroke; Structure; Technology; Testing; Therapeutic; Training; Training Programs; Translational Research; Woman; Work; career; career development; diabetes mellitus therapy; diabetes prevention program; experience; feeding; genetic variant; glucose metabolism; improved; innovation; insight; medical schools; metabolomics; non-diabetic; novel; novel strategies; patient oriented research; prevent; programs; research study; response; skills; skills training; working group

DESCRIPTION (provided by applicant): This application details a comprehensive five-year training program for mentored career development in patient-oriented research. The applicant completed clinical training in internal medicine at the Brigham and Women's Hospital and endocrinology at the Massachusetts General Hospital (MGH). Concurrent with his clinical training, he earned a Masters in Clinical and Translational Science from Harvard Medical School, conducted genetic research in type 2 diabetes (T2D) development, and applied metabolite profiling to study medication-induced changes in individuals at risk of T2D. He proposes a research program specifically constructed to provide focused training in translational metabolomics, genetic, and clinical intervention approaches that will serve as the foundation for his transition towards an independent career as a physician-scientist. The applicant aims to combine his prior training in clinical medicine, human physiology, metabolomics, and genetics with newly acquired skills within a structured environment to accomplish this goal. He has chosen mentors with complementary expertise: Dr. Jose Florez is an expert in human genetics and pharmacogenetics with a strong background in human physiology research, and he is Chair of the Diabetes Prevention Program Genetics Working Group; and Dr. Robert Gerszten is co-PI of the Metabolite Profiling Platform at the Broad Institute and Director of Translational Research at the MGH Heart Center. Both investigators have a strong record of mentorship with trainees progressing to scientific independence. The applicant's career development plan entails rigorous coursework and seminars, hands-on practical experience, and close guidance from a network of scientific advisors with diverse scientific expertise yet uniform commitment to the career development of the applicant. The scientific aims of this application are to: 1. derive the pharmacometabolite signature of acute and chronic metformin response; 2) integrate genetics and metabolomics to characterize metabolic factors of metformin response; and 3) modulate the pharmacometabolite signature of metformin response through clinical intervention. To accomplish these aims, the applicant will utilize state-of-art metabolomic and genomic platforms at the Broad Institute to assess metabolite levels and associated genetic loci in the Diabetes Prevention Program (DPP), a completed clinical trial that identified metformin as an effective strategy for T2D prevention, and the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans, a novel pharmacogenetic and metabolomics resource, which he has helped develop over the past 5 years. These aims will identify metabolic factors that influence metformin response, characteristics of individuals who are most likely to benefit from this preventive intervention, and targets for novel T2D prevention strategies. Collectively, the experience gained during this award will serve as the foundation for the applicant's independent, academic career as a physician-scientist with expertise in translational research in human metabolic disease and a mission of improving strategies for T2D prevention and treatment.

描述（由申请人提供）：本申请详细介绍了一项为期五年的综合培训计划，用于以患者为导向的研究中指导职业发展。申请人在布莱根妇女医院完成了内科临床培训，在马萨诸塞州总医院 (MGH) 完成了内分泌科临床培训。在接受临床培训的同时，他获得了哈佛医学院的临床和转化科学硕士学位，开展了 2 型糖尿病 (T2D) 发展的基因研究，并应用代谢物分析来研究药物引起的 T2D 风险个体的变化。他提出了一个专门构建的研究计划，旨在提供转化代谢组学、遗传和临床干预方法方面的集中培训，这将成为他向作为一名医师科学家的独立职业过渡的基础。申请人的目标是将他之前在临床医学、人体生理学、代谢组学和遗传学方面的培训与在结构化环境中新获得的技能相结合，以实现这一目标。他选择了具有互补专业知识的导师：Jose Florez 博士是人类遗传学和药物遗传学方面的专家，具有深厚的人类生理学研究背景，并且是糖尿病预防计划遗传学工作组的主席； Robert Gerszten 博士是 Broad 研究所代谢物分析平台的联合 PI 和 MGH 心脏中心转化研究主任。两位研究人员都有良好的指导学员走向科学独立的记录。申请人的职业发展计划需要严格的课程和研讨会、实践经验以及科学顾问网络的密切指导，这些顾问拥有不同的科学专业知识，但对申请人的职业发展有着统一的承诺。本申请的科学目的是： 1. 得出急性和慢性二甲双胍反应的药物代谢物特征； 2）整合遗传学和代谢组学来表征二甲双胍反应的代谢因素； 3) 通过临床干预调节二甲双胍反应的药物代谢特征。为了实现这些目标，申请人将利用布罗德研究所最先进的代谢组学和基因组平台来评估糖尿病预防计划（DPP）中的代谢物水平和相关遗传位点，该计划是一项已完成的临床试验，确定二甲双胍是一种有效的策略预防 T2D 的工作，以及了解人类对二甲双胍和格列吡嗪急性反应遗传学的研究，这是他在过去 5 年中帮助开发的一种新型药物遗传学和代谢组学资源。这些目标将确定影响二甲双胍反应的代谢因素、最有可能从这种预防性干预措施中受益的个体的特征，以及新型 T2D 预防策略的目标。总的来说，在该奖项期间获得的经验将为申请人作为一名医学科学家的独立学术生涯奠定基础，该申请人拥有人类代谢疾病转化研究的专业知识，并以改进 T2D 预防和治疗策略为使命。