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

描述（由申请人提供）：该候选人的直接职业目标是加快目前正在进行的研究作为他的博士后培训的一部分，并加强他的职业发展，使他能够成功过渡到一个独立的职业生涯在老龄化研究。目前和拟议的研究重点是区分IGF-1对能量平衡，胰岛素作用，健康衰老和长寿的中枢和外周作用。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，短期内将专注于遗传学和神经生物学的强化课程和实践培训，以及一个神经科学家指导委员会，将帮助监督候选人的研究和培训。该提案的长期职业目标是使候选人作为新的首席研究员，获得受保护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，并开发一种新的研究路线，产生强大的赠款提案，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，这表明了有利于衰老的新作用。这与外周IGF-1相反，它的好作用也有“坏”作用，例如增加癌症风险。在这个提议中，我们将试图进一步剖析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，健康的衰老和长寿最好通过增加下丘脑中的IGF-1作用来获得“好”的效果，同时减少外周中的IGF-1作用来最大限度地减少“坏”的影响，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。候选人设计了三个具体的目标，在授予期间执行，以测试整体假设。本提案的目的1将集中于区分急性IGF-1作用在调节外周葡萄糖代谢中随衰老的中枢与外周效应，并将致力于利用包括使用新型基因工程小鼠在内的策略组合在下丘脑中建立机制。该提案的目的2将集中于区分慢性IGF-1作用在调节葡萄糖和能量稳态与衰老的中枢和外周效应，并将利用脑中诱导型IGF-1过表达的大鼠模型和小鼠模型。目标3的目标是研究慢性中枢IGF-1过表达的终身影响，通过慢病毒靶向下丘脑内侧基底和/或终身外周IGF-1受体阻滞剂对大鼠的健康衰老和寿命。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职业目标，并阐明了与IGF- 1作用和衰老相关的新颖而重要的机制。 公共卫生相关性：在模式生物中，胰岛素/IGF信号传导减少与寿命延长有关，但在人类中，与胰岛素抵抗、骨质疏松症、心血管疾病和内脏肥胖有关，我们最近发现了中枢IGF-1作用对外周代谢的新的积极影响，并建议旨在“打破IGF-1平衡”的策略。从外周到中枢的1个动作可以最大限度地发挥IGF-1的“良好”作用，同时最大限度地降低癌症风险，以促进健康衰老和长寿。

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.