SIRT1-MEDIATED CENTRAL ADAPTATION TO DIET RESTRICTION

SIRT1 介导的中枢饮食限制适应

基本信息

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
项目类别：
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

项目摘要

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）：对饮食摄入改变的生理反应如何影响衰老和寿命的过程是一个基本问题，以了解代谢与衰老之间复杂联系的系统性调节。饮食限制（DR）是已知的单一，最可靠的方案，可在各种生物体中延迟衰老并延长寿命，为解决这个重要问题提供了独特的模型。该研究建议旨在了解对DR的生理适应性反应的分子机制，尤其是哺乳动物中心的自适应反应。我们对NAD依赖性脱乙酰基酶/ADP-核糖基转移酶的进化保守的SIR2（无声信息调节剂2）感兴趣，也称为“ Sirtuins”，是协调对DR的生理反应的关键调节剂。 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,由Dr诱导。因此，在此提案中，我们假设SIRT1通过OX2R表达的上调和DHM和LH中的神经激活来控制对DR的中心适应性反应，包括增强体育活动和体温的维持。为了解决这一假设，我们将研究1）SIRT1如何通过新鉴定的目标同源域转录因子在响应DR的新目标中上调OX2R基因的转录，2）2）and虫注射是否表达SHRNA对SIRT1或SIRT1的sirt1靶标转录的andiviruse是对DMH和/或LH的ARVITIVES的AR DRH响应的RHIP dr.在DMH和LH中，以及4）SIRT1介导的中央自适应反应是否对于控制小鼠的寿命也很重要。由于对DR的中心自适应机制知之甚少，因此拟议的研究将提供对策划对DR的反应的生理机制的关键见解，并可以确保哺乳动物的寿命。