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

外周与中枢 IGF-1 在能量平衡和 lo 调节中的作用

• 批准号: 8111638
• 负责人: DEREK Major HUFFMAN
• 金额: $ 8.98万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111638
• 关键词: Accounting; Acute; Aging; Animals; Applications Grants; Award; Body fat; Brain; Cardiac; Cardiovascular Diseases; Cause of Death; 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-Like Growth Factor I; Knock-out; Link; Longevity; Malignant Neoplasms; Measures; Mediating; Mentors; 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

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.

描述（由申请人提供）：该候选人的近期职业目标是加快目前作为博士后培训一部分进行的研究，并加强他的职业发展，使他能够成功过渡到衰老研究领域的独立职业。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影响。因此，该提案将要求候选人发展并加强其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，设计了一个为期 5 年的职业发展计划，短期内将侧重于遗传学和神经生物学方面的强化课程工作和实践培训，以及一个由神经科学家组成的指导委员会，该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能够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，建立新的合作并开发新颖的系列研究产生强有力的拨款提案以确保独立资金。该候选人和他的实验室最近发现了中枢 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，这表明有利于衰老的新作用。这与外周 IGF-1 形成鲜明对比，外周 IGF-1 的好作用也有“坏”作用，例如增加癌症风险。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，包括中枢与外周影响。该研究计划的总体假设是，健康老龄化和长寿的最佳实现方式是增加下丘脑中的 IGF-1 作用以获得“良好”效果，同时减少外周 IGF-1 的作用以最大程度地减少“坏”影响，即癌症。最终，这些研究可能会就 IGF-1 对人类健康和衰老的复杂作用产生重要的新见解。候选人设计了三个在奖励期间要执行的具体目标，以检验总体假设。该提案的目标 1 将侧重于区分急性 IGF-1 作用在调节外周葡萄糖代谢随衰老过程中的中枢效应和外周效应，并将致力于利用多种策略的组合在下丘脑中建立机制，包括使用新型基因工程小鼠。该提案的目标 2 将侧重于区分慢性 IGF-1 作用在调节衰老过程中的葡萄糖和能量稳态中的中枢和外周效应，并将利用大脑中诱导型 IGF-1 过度表达的大鼠模型和小鼠模型。目标 3 的目标是研究针对下丘脑内侧基底的慢病毒慢性中枢 IGF-1 过表达和/或终生外周 IGF-1 受体阻断对大鼠健康衰老和寿命的终生影响。在 K99/R00 奖结束时，候选人期望实现其短期和长期职业目标，并阐明与 IGF-1 作用和衰老相关的新颖且重要的机制。 公共健康相关性：项目叙述在模型生物体中，胰岛素/IGF 信号传导减少与寿命延长相关，但在人类中，却与胰岛素抵抗、骨质疏松症、心血管疾病和内脏肥胖矛盾地相关。我们最近发现了中枢 IGF 的新积极作用-1 对外周代谢的作用，并表明旨在从外周到中枢“平衡”IGF-1 作用的策略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促进健康老龄化和长寿。