Peripheral versus central IGF-1 action in the modulation of energy balance and lo

描述（由申请人提供）：该候选人的近期职业目标是加快目前正在进行的研究，作为他博士后培训的一部分，并加强他的职业发展，使他能够成功地过渡到一个独立的老龄研究职业。目前和未来的研究主要集中在区分IGF-1在能量平衡、胰岛素作用、健康衰老和长寿方面的中枢和外周作用。因此，该提案将要求候选人发展和加强他在遗传学和神经科学方面的培训，以便成功地参与该提案的某些方面。与他的导师合作，设计了一个5年的职业发展计划，短期内将集中在遗传学和神经生物学方面的强化课程和实践培训，以及一个由神经科学家组成的指导委员会，将帮助监督候选人的研究和培训。这项建议的长期职业目标是使候选人，作为一个新的首席研究员，有保障的时间来发展他的研究团队，提高他培训研究员和学生的能力，建立新的合作关系，并开发一个新的研究线，产生强有力的拨款申请，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作用的显著积极作用，包括改善外周胰岛素作用和选择性消耗内脏脂肪，这表明了有利于衰老的新作用。这与外周IGF-1形成对比，在外周IGF-1中，它的良好影响也有“坏”影响，比如增加癌症风险。在本提案中，我们将尝试进一步剖析IGF-1对衰老的“好”和“坏”影响，包括中枢效应和外周效应。该研究计划的总体假设是，通过增加下丘脑中IGF-1的作用来获得“好的”效果，同时减少周围的IGF-1作用以最大限度地减少“坏的”效果，即癌症，可以最好地实现健康的衰老和长寿。最终，这些研究可能会对IGF-1在人类健康和衰老中的复杂作用产生重要的新见解。候选人设计了三个具体的目标，要执行在奖励期间，以检验整体假设。本提案的目的1将侧重于区分急性IGF-1作用在调节衰老的外周糖代谢中的中枢作用和外周作用，并将利用包括使用新型基因工程小鼠在内的多种策略来建立下丘脑的机制。本提案的目的2将集中于区分慢性IGF-1在调节葡萄糖和能量稳态中的中枢和外周作用，并将利用大鼠模型和小鼠模型诱导IGF-1在大脑中过表达。Aim 3的目标是研究针对中基底下丘脑的慢病毒慢性中枢性IGF-1过表达和/或终身外周IGF-1受体阻断对大鼠健康衰老和长寿的终身影响。在K99/R00奖项结束时，候选人希望实现其短期和长期的职业目标，并阐明与IGF- 1作用和衰老相关的新颖和重要的机制。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Project Narrative In model organisms, reduced insulin/IGF signaling is associated with improved longevity, but in humans, is paradoxically associated with insulin resistance, osteoporosis, cardiovascular disease and visceral obesity, We have recently uncovered novel positive effects of central IGF-1 action on peripheral metabolism and suggest that strategies designed to "tip the balance" of IGF-1 action from peripheral to central may maximize the 'good' effects of IGF-1 while minimizing cancer risk to promote healthy aging and longevity.