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

基本信息

批准号：
8821073
负责人：
Geoffrey A. Walford
金额：
$ 14.39万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/8821073
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 Heart Heart Diseases Hospitals Human Human Genetics Incidence Individual Institutes Internal Medicine Intervention Lead Massachusetts 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 public health relevance research study response skills skills training working group

项目摘要

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）：此申请详细介绍了一项全面的为期五年的培训计划，用于以患者为导向的研究中的职业发展。申请人在马萨诸塞州总医院（MGH）的杨百翰和妇女医院和内分泌学完成了内科临床培训。同时，他在临床培训中获得了哈佛医学院的临床和转化科学硕士学位，对2型糖尿病（T2D）发育进行了遗传研究，并应用了代谢物分析，以研究患有T2D风险的人的药物诱导的人的变化。他提出了一项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的重点培训，该方法将成为他过渡到独立职业医生 - 科学家的基础。申请人旨在将他先前在临床医学，人类生理学，代谢组学和遗传学方面的培训与结构化环境中新获得的技能结合在一起，以实现这一目标。他选择了具有互补专业知识的导师：何塞·弗洛雷斯（Jose Florez）博士是人类遗传学和药物遗传学专家，在人类生理学研究方面具有强大的背景，他是糖尿病预防计划遗传学工作组的主席；罗伯特·格斯茨（Robert Gerszten）博士是Broad Institute代谢物分析平台的Co-Pi，也是MGH心脏中心转化研究主任。两位调查人员都有良好的指导记录，学员们晋升为科学独立性。申请人的职业发展计划包括严格的课程和研讨会，实践经验以及来自具有多种科学专业知识但对申请人职业发展的科学顾问网络的密切指导。该应用的科学目的是：1。得出急性和慢性二甲双胍反应的药代代谢物特征； 2）整合遗传学和代谢组学以表征二甲双胍反应的代谢因子； 3）通过临床干预调节二甲双胍反应的药物代谢物特征。为了实现这些目的，申请人将在广泛研究所使用最先进的代谢组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的遗传基因座（DPP），这是一项完整的临床试验，该试验确定了二甲甲状腺素，确定二甲甲呈元素作为T2D预防的有效策略，并了解了遗传学，并了解了entermin and gromist of entume intrife and gromint intrife and gromint intrift and-Glip，又有敏捷的疾病，并获得了敏锐的敏锐响应。代谢组学资源，他在过去5年中帮助发展了。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中受益的个体的特征以及针对新型T2D预防策略的目标。总的来说，在该奖项期间获得的经验将成为申请人独立的学术生涯的基础，该职业生涯是一名医师科学家，具有人类代谢疾病转化研究的专业知识，并成为改善T2D预防和治疗策略的使命。