Using Optogenetics to Dissect the Role of Redox Signaling During C. Elegans Aging

利用光遗传学剖析线虫衰老过程中氧化还原信号的作用

• 批准号: 9751694
• 负责人: Jason M. Held
• 金额: $ 19.61万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751694
• 关键词: Address; Affect; Aging; Animal Model; Animals; Antioxidants; Biology; Caenorhabditis elegans; Cell Nucleus; Cell membrane; Chemistry; Complex; Cytoplasm; Development; Disease; Electron Transport; Electrons; Endoplasmic Reticulum; Free Radicals; Genetic; Genetic Transcription; Health; Human; Impairment; Intestines; Lead; Life Extension; Light; Location; Longevity; Mediating; Mitochondria; Mitochondrial Matrix; Modeling; Movement; Muscle; NADP; Neurons; Organelles; Oxidases; Oxidation-Reduction; Oxidative Stress; Pattern; Phenotype; Physiological; Play; Production; Proteins; Pump; Reactive Oxygen Species; Reagent; Regulation; Reporter; Reproduction; Research; Role; Second Messenger Systems; Signal Transduction; Site; Source; Techniques; Technology; Testing; Therapeutic; Time; Tissues; age related; design; experimental study; healthspan; improved; inhibitor/antagonist; innovation; mutant; novel; novel strategies; optogenetics; oxidation; programs; spatiotemporal; stem; supernova; theories; transcription factor

PROJECT SUMMARY The model that reactive oxygen species (ROS) cause age-related degeneration has been challenged by the observation that endogenously produced ROS are essential second messengers sufficient to extend lifespan in many model organisms. Seemingly contradictory results and regulatory models derived from manipulations of global ROS levels are commonly framed as the `antioxidant paradox' of aging12. A key observation is that long- lived mutant animals of several model organisms, including C. elegans, often require ROS for lifespan extension, which seems contrary to the free radical theory of aging that posits ROS are deleterious. We propose to address this paradox in the context of C. elegans longevity and aging. We hypothesize that the location and level of redox signaling is the critical determinant of whether ROS promote lifespan extension or cause age-related degeneration. To test this hypothesis, we will utilize an innovative new technique, optogenetic production of ROS, to systematically explore how the location, timing and intensity of intracellular ROS production affects C. elegans lifespan, healthspan and transcriptional programs. Aim 1 will define the locations, both at the subcellular and tissue level, that are sufficient for C. elegans lifespan extension. Aim 2 will determine how spatial regulation of ROS production controls activation of lifespan extending transcriptional programs. The ability to precisely control ROS production with optogenetics will enable us for the first time to disentangle how redox signaling networks functionally contribute to complex phenotypes such as aging. Successful completion of these aims will have a significant impact by elucidating the biology of redox signaling that influences lifespan and suggesting strategies to improve development and application of antioxidants as possible therapeutics for aging and age-related disease.

项目摘要 活性氧（ROS）导致年龄相关性退化的模型受到了来自 观察到内源性产生的活性氧是必要的第二信使，足以延长寿命， 许多模式生物。看似矛盾的结果和监管模式来自操纵 全球活性氧水平通常被认为是衰老的“抗氧化剂悖论”12。一个关键的观察是，长期- 活的几种模式生物的突变动物，包括C.线虫，通常需要ROS来维持生命 延伸，这似乎与衰老的自由基理论相反，该理论假定ROS是有害的。我们 建议在C. elegans长寿和衰老。我们假设 氧化还原信号的位置和水平是ROS是否促进寿命延长或 会导致衰老为了验证这一假设，我们将利用一种创新的新技术， ROS的光遗传学产生，以系统地探索细胞内ROS的位置，时间和强度， ROS的产生影响C. elegans寿命，healthspan和转录程序。目标1将定义 位置，无论是在亚细胞和组织水平，这是足够的C。elegans寿命延长。目的2 将决定ROS产生的空间调节如何控制寿命延长转录因子的激活， 程序.利用光遗传学精确控制ROS产生的能力将使我们首次能够 解开氧化还原信号网络如何在功能上有助于复杂的表型，如老化。 这些目标的成功完成将通过阐明氧化还原信号的生物学产生重大影响 影响寿命，并提出改善抗氧化剂开发和应用的策略， 可能的衰老和年龄相关疾病的治疗方法。