Physiology of Lifespan Extension and Metabolic Hormesis with Riboflavin Depletion

核黄素消耗延长寿命和代谢兴奋作用的生理学

基本信息

批准号：
10663638
负责人：
Armen I Yerevanian
金额：
$ 16.92万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663638
关键词：
Address Adipocytes Advisory Committees Aging Animal Model Animals Area Automobile Driving Biological Assay Biological Availability Biology Biology of Aging Body Composition Caenorhabditis elegans Caloric Restriction Cell Line Cells Cellular biology Characteristics Data Disease Doctor of Philosophy Dose Down-Regulation Environment Enzymes FOXO1A gene Five-Year Plans Flavin Mononucleotide Flavin-Adenine Dinucleotide Flavins Functional disorder Funding General Hospitals Goals Health Benefit Hepatic Hepatocyte Human Insulin Resistance Lipids Longevity Mammals Massachusetts Mediating Medicine Mentors Metabolic Metabolic Diseases Metabolic Pathway Metabolism Micronutrients Mitochondria Modeling Molecular Mus Nematoda Neurodegenerative Disorders Obesity Organism Orthologous Gene Oxidases Oxidation-Reduction Pathway interactions Pharmacology Phenotype Physicians Physiological Physiology Process Production Reactive Oxygen Species Regulation Research Research Personnel Respiration Riboflavin Role Scientist Signal Transduction Succinate Dehydrogenase Therapeutic Time Tissues Training Vocational Guidance Work Yeasts biological adaptation to stress career development cofactor functional genomics healthspan healthy aging insight knock-down lipid metabolism medical schools member mid-career faculty mimetics mouse model new therapeutic target novel oxidation professor programs protective effect response skills therapeutic target tool translational model translational potential uptake

项目摘要

This proposal describes a five-year plan for Armen Yerevanian MD to transition to an independently-funded investigator with expertise in the metabolism of aging and the molecular physiology of riboflavin. He will be mentored by Alexander Soukas MD PhD, Associate Professor of Medicine at Harvard Medical School and an expert in both functional genomics and the biology of C. elegans. He will be co-mentored by Marcia Haigis PhD, Professor of Cell Biology at Harvard Medical School and a member of the Paul F. Glenn Center for the Biology of Aging. An advisory committee of physician-scientists with expertise in human aging, C. elegans aging, and metabolism have been assembled, including Gary Ruvkun PhD, Keith Blackwell MD PhD, Jose Florez MD PhD, and Richard Lee MD to provide scientific direction and career guidance during the transition to independence. Dr. Yerevanian will carry out the planned career development activities in the research and training environment at the Massachusetts General Hospital and Harvard Medical School. This research program utilizes the organism C. elegans, murine cell lines and mouse models to examine the physiology of riboflavin depletion and identify the core molecular mechanisms that underpin the lifespan extending effects of riboflavin depletion in C. elegans. The biology of riboflavin utilization and transport is strongly conserved through metazoans, making it an attractive area to study as a translational target. The ability to modulate cellular energetics and metabolic hormesis through riboflavin depletion may provide key therapeutic targets for the complications of aging, particularly metabolic complications including insulin resistance, changes in body composition and neurodegenerative diseases. Preliminary studies have already shown that riboflavin depletion extends lifespan in C. elegans, and utilizes canonical pathways associated with longevity including AMPK and FOXO. We hope to further elucidate the metabolic regulators of this process, including flavin co- factor synthesis, mitochondrial energetics, and lipid metabolism. The investigator will utilize functional genomics of C. elegans, metabolic assays of enzyme regulation, and novel mechanisms for altering cellular energetics to explore these aims. The ultimate goal of this work is to characterize the fundamental biology of riboflavin depletion, promote metabolic hormesis and healthy aging via riboflavin depletion in translational models, and to transition to independent investigator status.

该提案描述了Armen Yerevanian MD的五年计划，以过渡到独立资金研究人员具有衰老代谢和核黄素分子生理学的专业知识。他会的由哈佛医学院医学副教授亚历山大·索卡斯（Alexander Soukas）指导功能基因组学和秀丽隐杆线虫生物学的专家。他将由玛西娅·海吉斯（Marcia Haigis）博士学位哈佛医学院细胞生物学教授和保罗·格伦·格伦（Paul F. Glenn）生物学中心的成员衰老。具有专业知识的医师科学家咨询委员会，秀丽隐杆线虫的衰老和已经组装了新陈代谢，包括Gary Ruvkun博士，Keith Blackwell MD博士，Jose Florez MD博士理查德·李（Richard Lee）在过渡到独立性期间提供科学方向和职业指导。埃里瓦尼亚博士将在研究和培训环境中开展计划的职业发展活动在马萨诸塞州综合医院和哈佛医学院。该研究计划利用有机体秀丽隐杆线虫，鼠细胞系和小鼠模型来检查核黄素耗竭的生理学，并识别支撑寿命的核心分子机制扩展果岭核黄素耗竭的影响。核黄素利用和运输的生物学强烈通过后生动物保守，使其成为一个具有转化目标的吸引力的领域。能力通过核黄素耗竭调节细胞能量和代谢荷兰可能会提供关键的治疗性衰老并发症的靶标，尤其是代谢并发症，包括胰岛素抵抗，变化在身体组成和神经退行性疾病中。初步研究已经表明核黄素耗竭延长了秀丽隐杆线虫的寿命，并利用与寿命相关的规范途径 Ampk和Foxo。我们希望进一步阐明该过程的代谢调节剂，包括黄素共同因子合成，线粒体能量和脂质代谢。研究者将利用功能基因组学秀丽隐杆线虫，酶调节的代谢测定法以及改变细胞能量的新机制探索这些目标。这项工作的最终目标是表征核黄素的基本生物学在翻译模型中，通过核黄素耗竭的耗竭，促进代谢荷尔特和健康衰老，并过渡到独立调查员身份。