SIRT1-MEDIATED CENTRAL ADAPTATION TO DIET RESTRICTION

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新陈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)是已知的在各种生物体中延缓衰老和延长寿命的单一、最可靠的养生方法，它为解决这一重要问题提供了一个独特的模式。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NAD依赖的脱乙酰酶/ADP核糖基转移酶家族Sir2(沉默信息调节因子2)感兴趣，它也被称为sirtuins，作为协调对DR的生理反应的关键调节因子。我们的新研究最近证明了哺乳动物Sir2同源SIRT1在下丘脑，特别是在下丘脑背内侧和外侧核(分别为DMH和LH)中的一种新功能，作为控制增食欲素2型受体(OX2R)的关键介质，在包括Ghrelin在内的外周信号的反应中，Ghrelin是一种从胃分泌的促食欲素激素。因此，在本提案中，我们假设SIRT1控制中枢对DR的适应性反应包括增加体力活动和维持体温，通过上调Ox2r的表达和激活DHM和LH区的神经。为了解决这一假说，我们将探讨1)SIRT1如何通过新发现的同源异域转录因子上调Ox2r基因的转录；2)针对Sirt1或SIRT1靶区转录因子的慢病毒立体定向注射是否可抑制针对Sirt1或SIRT1靶区转录因子的shRNA进入DMH和/或LH；3)DR如何增强DMH和LH中SIRT1的活性；4)SIRT1介导的中央适应性反应是否对于控制小鼠的寿命也很重要。由于对DR的中枢适应机制知之甚少，这项拟议的研究将为协调对DR的反应的生理机制提供关键的见解，并可能确保哺乳动物的长寿。

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.