Impact of FGF21 on healthspan and lifespan

项目概要： 这项计划项目补助金（PPG）的建议旨在了解新的亲的作用机制， 通过在耶鲁大学组建一个多样化和互补的研究小组， 大学和UT西南。成纤维细胞生长因子21（FGF 21）是内分泌FGF家族的成员， 通过由FGF受体组成的细胞表面受体与专性共 受体β Klotho。FGF21是一种独特的代谢激素，因为它响应于代谢而从肝脏分泌到血液中。 饥饿和营养缺乏刺激脂肪酸氧化和维持能量平衡。最近 我们PPG团队的研究已经证明小鼠中FGF 21的过表达延长了寿命， 改善胰岛素敏感性，并可能促进免疫功能。根据这些数据， 这个项目的目的是，FGF21是中枢神经系统-脂肪组织-免疫系统相互作用的关键驱动因素， 协同推进长寿分子计划。本项目的总体目标是阐明 FGF21抗衰老作用的分子机制，并利用这些见解来抑制 与衰老有关的慢性疾病。鉴于研究团队的不同背景和技能，我们可以使用 评估FGF 21对多器官系统的影响的最先进的小鼠模型和方法， 从分子到行为的不同层次。我们建议推行四项计划， 本PPG：在Steven Kliewer博士和大卫Mangelsdorf博士的领导下，项目1将调查 FGF21对生长激素作用、健康寿命和寿命的影响。项目2在博士的领导下。 Vishwa Deep Diagnosis将研究FGF 21介导的免疫代谢相互作用对免疫系统的影响。 衰老项目3将由Philipp谢勒博士领导，以研究FGF 21的影响， 脂联素-神经酰胺轴对衰老的影响，项目4在Tamas Horvath博士的领导下将研究 FGF 21对CNS和下丘脑衰老控制影响。核心A将促进通信 核心B将提供集中的分析设施 衰老和健康寿命的关系。PPG团队将探索新的假设，即FGF21通过 多种组织，以增加健康和寿命。

PROJECT SUMMARY: This proposal for a program project grant (PPG) seeks to understand the mechanism of action of the novel pro- longevity hormone FGF21 by assembling a diverse and complementary group of investigators at Yale University and UT Southwestern. Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF subfamily that acts through a cell surface receptor composed of FGF receptors in complex with the obligate co- receptor βKlotho. FGF21 is a unique metabolic hormone as it is secreted in blood from liver in response to starvation and nutrient deprivation to stimulate fatty acid oxidation and to maintain energy balance. Recent studies from our PPG team have demonstrated that overexpression of FGF21 in mice extends lifespan, improves insulin-sensitivity and may promote immune function. Based on these data, the central hypothesis of this program project is that FGF21 is a key driver of CNS-adipose tissue-immune system interactions that coordinately promote a prolongevity molecular program. Overall objective of this project is to elucidate the molecular mechanisms underlying FGF21's anti-aging effects and to leverage these insights towards inhibiting aging-related chronic diseases. Given the diverse backgrounds and skills of the research team, we can use state-of-the-art mouse models and methodology to assess the effects of FGF21 on multiple organ systems at different levels ranging from the molecular to the behavioral. We propose four projects to pursue the aims of this PPG: Project 1 under the leadership of Drs. Steven Kliewer and David Mangelsdorf will investigate the impact of FGF21 on growth hormone action, healthspan and lifespan. Project 2 under the leadership of Dr. Vishwa Deep Dixit will study the impact of FGF21-mediated immune-metabolic interactions on immune- senescence. The project 3 will be headed by Dr. Philipp Scherer to investigate the Impact of FGF21- adiponectin-ceramide axis on aging and Project 4 under the leadership of Dr. Tamas Horvath will study the impact of FGF21 on CNS and hypothalamic control of aging. The Core A will facilitate communications between projects and provide support for data analyses and Core B will provide centralized facility for analysis of aging and healthspan in mice. The PPG team will explore the novel hypothesis that FGF21 acts through multiple tissues to increase healthspan and lifespan.