Peripheral and central IGF-1 action in energy balance and longevity modulation

外周和中枢 IGF-1 在能量平衡和寿命调节中的作用

• 批准号: 8655133
• 负责人: DEREK Major HUFFMAN
• 金额: $ 24.65万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8655133
• 关键词: Accounting; Acute; Aging; Animal Model; Animals; Applications Grants; Award; Body fat; Brain; Cardiac; Cardiovascular Diseases; Cause of Death; Central obesity; Chronic; Clinical; Clinical assessments; Collaborations; Complex; Data; Development; Development Plans; Energy Metabolism; Environment; Equilibrium; Exercise; Fatty acid glycerol esters; Funding; Gene Expression; Genetic; Genetically Engineered Mouse; Glucose; Goals; Health; Homeostasis; Human; Hybrids; Hypothalamic structure; Inbred BN Rats; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Knock-out; Link; Longevity; Malignant Neoplasms; Measures; Mediating; Mentors; Metabolism; Modeling; Morbidity - disease rate; Neuraxis; Neurobiology; Neurosciences; Non-Insulin-Dependent Diabetes Mellitus; Osteoporosis; Pathologic; Peripheral; Phase; Principal Investigator; Pump; Rattus; Research; Research Personnel; Research Training; Risk; Role; Secure; Signal Transduction; Site; Somatotropin; Students; Subfamily lentivirinae; Technology; Testing; Time; Training; Viral; Visceral; Work; cancer risk; cancer therapy; career; career development; cognitive function; cohort; design; energy balance; frailty; glucose metabolism; healthy aging; improved; in vivo; insight; male; mortality; mouse model; novel; overexpression; post-doctoral training; receptor; research study

Proposal Summary The immediate career goal of this candidate is to expedite the research currently being conducted as part of his postdoctoral training and to enhance his career development to enable his successful transition to an independent career in aging research. The current and proposed research is focused on distinguishing the central and peripheral effects of IGF-1 on energy balance, insulin action, healthy aging and longevity. As such, this proposal will require that the candidate develops and enhances his training in both genetics and neuroscience in order to successfully engage some facets of this proposal. In collaboration with his mentor, a 5-year career development plan has been designed which in the short-term will focus on intensive course work and hands-on training in genetics and neurobiology, and a mentoring committee of neuroscientists that will help to oversee the candidate's research and training. The long-term career goals of this proposal are to enable the candidate, as a new principal investigator, to secure protected time to develop his research team, to enhance his ability to train fellows and students, establish new collaborations and develop a novel line of research which produces strong grant proposals to secure independent funding. The candidate and his lab have recently uncovered remarkable positive effects of central IGF-1 action including improved peripheral insulin action and selective depletion of visceral fat, suggesting novel actions that are favorable for aging. This is in contrast to peripheral IGF-1, where among its good effects are also 'bad' effects, such as raising cancer risk. In this proposal, we will attempt to further dissect the 'good' and 'bad' effects of IGF-1 on aging, including central versus peripheral effects. The overall hypothesis of the research plan is that healthy aging and longevity is best achieved by increasing IGF-1 action in the hypothalamus to reap the 'good' effects while decreasing it in the periphery to minimize the 'bad' effects, namely cancers. Ultimately, these studies may yield important new insights regarding the complex role of IGF-1 on health and aging with relevance to humans. The candidate has devised three specific aims to be performed during the award period in order to test the overall hypothesis. Aim 1 of this proposal will focus on distinguishing between the central versus peripheral effects of acute IGF-1 action in regulating peripheral glucose metabolism with aging and will work toward establishing the mechanism(s) in the hypothalamus utilizing a combination of strategies including the use of novel genetically-engineered mice. Aim 2 of this proposal will focus on distinguishing between the central and peripheral effects of chronic IGF-1 action in regulating glucose and energy homeostasis with aging and will utilize both the rat model and a mouse model of inducible IGF-1 overexpression in the brain. The goal of Aim 3 will be to study the lifelong effects of chronic central IGF-1 overexpression by lentivirus targeted to the mediobasal hypothalamus and/or lifelong peripheral IGF-1 receptor blockade on healthy aging and longevity in rats. At the conclusion of the K99/R00 award, the candidate expects to have achieved his short-term and long-term career goals and to have elucidated novel and significant mechanisms relevant to IGF- 1 action and aging.

建议总结