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）导致与年龄相关的变性的模型受到了挑战 观察到内源产生的ROS是必不可少的第二使者，足以延长寿命 许多模型生物。看似矛盾的结果和监管模型从对 全球ROS水平通常被构成为老化的“抗氧化悖论” 12。一个关键的观察是长期 包括秀丽隐杆线虫在内的几种模型生物的生活突变动物通常需要ROS才能寿命 扩展似乎与假定ROS的自由基衰老理论相反。我们 建议在秀丽隐杆线虫的长寿和衰老的背景下解决这个悖论。我们假设 氧化还原信号的位置和水平是ROS是促进寿命延长还是 导致与年龄有关的变性。为了检验这一假设，我们将利用一种创新的新技术， ROS的光遗传学产生，系统地探索细胞内的位置，时机和强度如何 ROS生产会影响秀丽隐杆线虫的寿命，健康范围和转录计划。 AIM 1将定义 在亚细胞和组织水平上的位置足以容纳秀丽隐杆线虫的寿命延伸。目标2 将确定ROS生产控制的空间调节如何激活寿命扩展转录 程序。通过光遗传学精确控制ROS生产的能力将使我们首次能够 解开氧化还原信号网络在功能上如何有助于复杂的表型，例如衰老。 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 这影响了寿命，并提出了改善抗氧化剂的开发和应用的策略 可能用于衰老和与年龄有关的疾病的治疗剂。