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: 8639145
• 负责人: DEREK Major HUFFMAN
• 金额: $ 24.9万
• 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/8639145
• 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.

建议书摘要 这位候选人的直接职业目标是加快目前正在进行的研究，如 博士后培训的一部分，并加强他的职业发展，使他能够成功 在老龄化研究方面过渡到独立的职业生涯。重点介绍了当前和未来的研究方向。 胰岛素样生长因子-1对能量平衡、胰岛素作用、健康的中枢和外周效应的区分 衰老和长寿。因此，这项提议将要求候选人发展和提高他的 在遗传学和神经科学方面进行培训，以便成功地参与其中的某些方面 求婚。与他的导师合作，设计了一个5年的职业发展计划 它在短期内将专注于密集的课程工作和遗传学和 神经生物学，以及一个神经科学家指导委员会，帮助监督候选人的 研究和培训。这项提议的长期职业目标是使候选人能够作为一名 新的首席调查员，以确保有保护的时间来发展他的研究团队，以加强他的 有能力培训研究员和学生，建立新的合作关系，开发新的研究方向 这产生了强有力的赠款建议，以确保独立的资金。候选人和他的实验室 最近发现了中枢IGF-1作用的显著积极影响，包括改善 外周胰岛素作用和选择性消耗内脏脂肪，提示新的作用是 有利于老化。这与外周血胰岛素样生长因子-1形成对比，后者的良好效果还包括 “坏”影响，比如增加患癌症的风险。在这个提案中，我们将尝试进一步剖析“好” IGF-1对衰老的“坏”影响，包括中枢和外周的影响。整体而言 研究计划的假设是，健康的衰老和长寿最好的实现方式是 增加下丘脑中的IGF-1的作用以获得“好”的效果，同时减少它在 将“坏”影响降至最低的外围设备，即癌症。最终，这些研究可能会产生 关于IGF-1在健康和衰老中的复杂作用的重要新见解 人类。候选人设计了三个具体的目标，在颁奖期间将在 以检验整个假说。本提案的目标1将侧重于区分 急性IGF-1调节外周葡萄糖代谢的中枢和外周效应 随着年龄的增长，他将致力于建立下丘脑的机制(S)，利用 包括使用新型基因工程小鼠在内的多种策略的结合。目标2 提案将侧重于区分慢性IGF-1的中枢和外周影响 在调节血糖和能量平衡方面的作用随年龄增长而变化，并将利用大鼠模型和 可诱导的IGF-1在大脑中过度表达的小鼠模型。目标3的目标将是研究 靶向中层的慢病毒慢性中枢IGF-1过度表达的终生效应 下丘脑和/或终生外周IGF-1受体阻断对小鼠健康衰老和长寿的影响 老鼠。在K99/R00奖项结束时，候选人希望已经实现了他的短期目标 和长期职业目标，并阐明与IGF相关的新的和重要的机制- 1行动和衰老。