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

提案摘要 该候选人的近期职业目标是加快目前正在进行的研究， 他的博士后培训的一部分，并加强他的职业发展，使他的成功 过渡到老龄化研究的独立职业。目前和拟议的研究重点是 关于区分IGF-1对能量平衡、胰岛素作用、健康、 老化和长寿。因此，该提案要求候选人发展和提高其 在遗传学和神经科学方面的培训，以成功地从事这方面的一些方面， 提议与他的导师合作，设计了一个5年职业发展计划 短期内将侧重于遗传学方面的强化课程和实践培训， 神经生物学，和一个指导委员会的神经科学家，将有助于监督候选人的 研究和培训。本提案的长期职业目标是使候选人能够作为一名 新的首席研究员，以确保受保护的时间来发展他的研究团队，以提高他的 培养研究员和学生的能力，建立新的合作关系，并开发新的研究方向 它提出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 最近发现了中央IGF-1作用的显着积极作用，包括改善 外周胰岛素作用和选择性消耗内脏脂肪，这表明新的行动， 有利于衰老。这与外周IGF-1相反，在其良好的效果中， “坏”的影响，如增加癌症风险。在这个建议中，我们将试图进一步剖析“好” 以及IGF-1对衰老的“坏”影响，包括中枢效应和外周效应。整体 研究计划的假设是，健康的老龄化和长寿是最好的实现， 增加IGF-1在下丘脑的作用，以获得“好”的效果，同时减少它在下丘脑中的作用。 外围以最大限度地减少“不良”影响，即癌症。最终，这些研究可能会产生 关于IGF-1对健康和衰老的复杂作用的重要新见解， 人类候选人在颁奖期间制定了三个具体目标， 来检验整体假设。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与外周效应 随着年龄的增长，并将致力于建立机制（S）在下丘脑利用 这些策略包括使用新的基因工程小鼠。目标2 一项提案将重点区分慢性IGF-1的中枢和外周效应 在调节葡萄糖和能量稳态中的作用，并将利用大鼠模型和 一种脑中诱导型IGF-1过表达的小鼠模型。目标3的目标是研究 慢性中枢IGF-1过表达对中基底膜慢病毒的终身影响 下丘脑和/或终身外周IGF-1受体阻滞剂对健康衰老和长寿的影响 大鼠在K99/R 00奖项结束时，候选人预计已经实现了他的短期 和长期的职业目标，并阐明了与IGF-1相关的新的和重要的机制， 1动作和衰老。

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.