Nutrient Sensing and the Oxidative Stress Response

营养感应和氧化应激反应

• 批准号: 8321968
• 负责人: DANICA CHEN
• 金额: $ 30.84万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321968
• 关键词: Aging; Antioxidants; Cell Culture Techniques; Cells; Cues; Development; Diet; Dietary Intervention; Disease; Drug Metabolic Detoxication; Event; Excision; Foundations; Generations; Knockout Mice; Lead; Liver; Long-Chain-Acyl-CoA Dehydrogenase; Longevity; Mammals; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Monitor; Mus; Nutrient; Oxidative Stress; Play; Positioning Attribute; Process; Production; Reactive Oxygen Species; Regimen; Research; Respiration; Role; Signal Transduction; Solid; System; Testing; Tissues; Transgenic Mice; Up-Regulation; base; biological adaptation to stress; detection of nutrient; dietary restriction; drug development; experience; fatty acid oxidation; gain of function; human SOD2 protein; human disease; improved; insight; mouse model; novel strategies; oxidative damage; prevent; programs; response; sensor

DESCRIPTION (provided by applicant): Oxidative stress contributes substantially to numerous human diseases and aging. Dietary restriction (DR), a dietary regimen that ameliorates various diseases and extends lifespan, reduces the steady state levels of oxidative stress and damage. DR has been postulated to reduce oxidative stress by slowing metabolism, and thereby reducing mitochondrial generation of reactive oxygen species (ROS). Recent findings, however, indicate that mitochondrial activity increases during DR. Thus, the molecular mechanism underlying DR- induced reduction of oxidative stress remains elusive. The central hypothesis of this proposal is that, instead of passively slowing metabolism, DR triggers an active defense program involving a cascade of molecular regulators to reduce oxidative stress. Our recent finding that DR activates a nutrient sensor to reduce oxidative stress supports this hypothesis. We plan to greatly expand this initial finding to delineate the cascade that senses nutrient input to regulate the cellular oxidative stress status. We have established a DR mouse model and a cell culture model to study nutrient sensing and the oxidative stress response. Using the established system, we will elucidate the molecular events that result in either reduced production or improved removal of cellular ROS during DR. Using a gain-of-function approach, we will test the feasibility of activating these molecules to mimic the DR response and reduce oxidative stress. Collectively, these studies challenge the paradigm that DR reduces oxidative stress by passively slowing metabolism and highlight an active defense program provoked by a low calorie diet to reduce oxidative stress. The factors identified in our study are likely to play paramount roles in maintaining the cellular oxidative stress status and suggest new approaches to treat oxidative stress-related diseases and slow aging. The proposed studies will build a solid foundation for a dynamic research program that has a great potential for development: nutrient sensing and the oxidative stress response.

描述（由申请人提供）：氧化应激在很大程度上导致许多人类疾病和衰老。饮食限制（DR）是一种改善各种疾病并延长寿命的饮食方案，可降低氧化应激和损伤的稳态水平。DR已被假定为通过减缓代谢来减少氧化应激，从而减少活性氧（ROS）的线粒体产生。然而，最近的研究结果表明，在DR期间线粒体活性增加。因此，DR诱导的氧化应激减少的分子机制仍然难以捉摸。该提议的中心假设是，DR不是被动地减缓代谢，而是触发涉及级联分子调节剂的主动防御程序以减少氧化应激。我们最近的发现，DR激活营养传感器，以减少氧化应激支持这一假设。我们计划极大地扩展这一初步发现，以描绘感知营养输入以调节细胞氧化应激状态的级联反应。我们建立了DR小鼠模型和细胞培养模型来研究营养感应和氧化应激反应。使用已建立的系统，我们将阐明分子事件，导致减少生产或改善去除细胞活性氧在DR。使用功能获得的方法，我们将测试激活这些分子模拟DR反应和减少氧化应激的可行性。总的来说，这些研究挑战了DR通过被动减缓代谢来减少氧化应激的范式，并强调了低热量饮食引起的减少氧化应激的主动防御计划。在我们的研究中确定的因素可能在维持细胞氧化应激状态方面发挥重要作用，并提出了治疗氧化应激相关疾病和延缓衰老的新方法。拟议的研究将为具有巨大发展潜力的动态研究计划奠定坚实的基础：营养传感和氧化应激反应。