SIRT1-MEDIATED CENTRAL ADAPTATION TO DIET RESTRICTION

SIRT1 介导的中枢饮食限制适应

• 批准号: 8840861
• 负责人: SHIN-ICHIRO IMAI
• 金额: $ 30.23万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840861
• 关键词: ADP Ribose Transferases; Ablation; Address; Affect; Age; Aging; Aging-Related Process; Animals; Anorexia; Body Temperature; Brain; Cell Nucleus; Chemicals; Complex; Data; Deacetylation; Dietary intake; Elderly; Enzymes; Family; Fasting; Feeding behaviors; Female; Foundations; Genetic; Genetic Transcription; Genetically Engineered Mouse; Hormones; Human; Hypothalamic structure; Injection of therapeutic agent; Intervention; Journals; Lasers; Lateral Hypothalamic Nucleus; Light; Longevity; Maintenance; Mammals; Manuscripts; Measures; Mediating; Mediator of activation protein; Metabolism; Microdissection; Modeling; Molecular; Mus; Neurologic; Neurons; Neurosciences; Organism; Orthologous Gene; Pathology; Peripheral; Physical activity; Physiological; Play; Receptor Gene; Regimen; Regulation; Reporting; Research; Research Proposals; Role; Signal Transduction; Sirtuins; Staining method; Stains; Stomach; Subfamily lentivirinae; Transgenic Mice; Up-Regulation; anti aging; cohort; dietary restriction; feeding; ghrelin; homeodomain; hypocretin; in vivo; innovation; insight; interest; male; nicotinamide phosphoribosyltransferase; novel; overexpression; promoter; receptor; receptor expression; receptor-mediated signaling; relating to nervous system; research study; response; small hairpin RNA; transcription factor

DESCRIPTION (provided by applicant): How physiological responses to alterations in dietary intake affect the process of aging and longevity is a fundamental question to understand the systemic regulation of the complex connection between metabolism and aging. Diet restriction (DR), the single, most reliable regimen known to retard aging and extend lifespan in a variety of organisms, has provided a unique model to address this important question. This research proposal aims to understand molecular mechanisms underlying physiological adaptive responses to DR, particularly the central adaptive response, in mammals. We have been interested in the evolutionarily conserved SIR2 (silent information regulator 2) family of NAD-dependent deacetylases/ADP-ribosyltransferases, also called "sirtuins," as a critical regulator that coordinates physiological responses to DR. Our new study has recently demonstrated a novel function of the mammalian SIR2 ortholog SIRT1 in the hypothalamus, particularly in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), as a key mediator that controls the orexin type 2 receptor (OX2R)-mediated signaling in response to peripheral signals including ghrelin, an orexigenic hormone secreted from stomach, induced by DR. Therefore, in this proposal, we hypothesize that SIRT1 controls central adaptive responses to DR, including the augmentation of physical activity and the maintenance of body temperature, through the up-regulation of the Ox2r expression and the neural activation in the DHM and LH. To address this hypothesis, we will examine 1) how SIRT1 up-regulates the transcription of the Ox2r gene through a newly identified target homeodomain transcription factor in response to DR, 2) whether stereotactic injection of lentiviruses expressing shRNA against Sirt1 or the SIRT1 target transcription factor into the DMH and/or LH abrogates the central adaptive response to DR, 3) how SIRT1 activity is augmented by DR in the DMH and LH, and 4) whether SIRT1-mediated central adaptive response is also important for the control of longevity in mice. Because very little has been known about the central adaptive mechanism for DR, the proposed study will provide critical insights into the physiological mechanism that orchestrates responses to DR and may assure longevity in mammals.

描述（由申请人提供）：对饮食摄入量变化的生理反应如何影响衰老和寿命的过程是理解代谢和衰老之间复杂联系的系统调节的基本问题。饮食限制（DR）是已知的延缓衰老和延长多种生物体寿命的唯一、最可靠的方案，为解决这一重要问题提供了独特的模型。本研究旨在了解哺乳动物对DR的生理适应性反应，特别是中枢适应性反应的分子机制。我们一直对进化上保守的SIR 2我们的新研究最近证实了哺乳动物SIR 2直系同源物SIRT 1在下丘脑，特别是在下丘脑背内侧核和外侧核中的新功能（分别为DMH和LH），作为控制食欲素2型受体（OX 2 R）介导的信号传导的关键介质，其响应于外周信号，包括由DR诱导的胃分泌的促食欲激素ghrelin。因此，在该提议中，我们假设SIRT 1控制对DR的中枢适应性反应，包括通过上调DHM和LH中Ox 2 r表达和神经激活来增强体力活动和维持体温。为了解决这一假设，我们将研究1）SIRT 1如何通过新鉴定的靶同源结构域转录因子上调Ox 2 r基因的转录以响应DR，2）将表达针对Sirt 1或SIRT 1靶转录因子的shRNA的慢病毒立体定向注射到DMH和/或LH中是否消除了对DR的中枢适应性反应，3）SIRT 1活性如何被DMH和LH中的DR增强，以及4）SIRT 1介导的中枢适应性反应是否对小鼠寿命的控制也很重要。由于对DR的中枢适应机制知之甚少，因此拟议的研究将为协调DR反应的生理机制提供重要见解，并可能确保哺乳动物的长寿。