The role of mitochondria-lysosome crosstalk in health and aging

线粒体-溶酶体串扰在健康和衰老中的作用

• 批准号: 10382429
• 负责人: Koning Shen
• 金额: $ 11万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382429
• 关键词: Advisory Committees; Aging; Animal Model; Autophagocytosis; Award; Biological Assay; Biology; Caenorhabditis elegans; Cell Culture Techniques; Cells; Cellular Stress; Cellular Stress Response; Communication; Data; Defect; Development; Development Plans; Disease; Failure; Functional disorder; Genes; Genetic; Goals; Health; Health Promotion; Homeostasis; Human; Individual; Knowledge; Leadership; Link; Longevity; Lysosomes; Mediating; Mentorship; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mutagenesis; Mutation; Organelles; Organism; Outcome; Parkinson Disease; Pathway interactions; Phase; Physiological; Play; Proteins; Proton-Translocating ATPases; RNA Interference; RNA interference screen; Research; Research Personnel; Role; Route; Science; Signal Pathway; Signal Transduction; Specificity; Stress; Suppressor Mutations; System; Testing; Time; Tissues; Work; Writing; Yeasts; age related; biological adaptation to stress; career; career development; experimental study; genetic manipulation; genome-wide; healthy aging; improved; innovation; insight; knock-down; loss of function; metabolomics; mutant; next generation sequencing; novel; proteostasis; response; skills; therapeutic development; transcriptome sequencing; vacuolar H+-ATPase; young adult

PROJECT SUMMARY/ABSTRACT The decline of health in aging has long been associated with dysfunctional mitochondria and lysosomes, but whether the failure of these two organelles is linked remains unclear. The overall goal of this application is to delineate how mitochondria and lysosomes communicate with each other to promote health in aging. The central hypothesis is that mitochondria and lysosomes normally communicate with each other to promote health, but this becomes compromised during aging, leading the two organelles to co-devolve into dysfunction. This is supported by preliminary data showing that defective lysosomes can activate a mitochondrial stress pathway in young adult C. elegans. The rationale is that in many aging conditions like Parkinson's disease, both mitochondria and lysosomes are defective or have familial mutations. If communication between mitochondria and lysosomes is important, the health decline with aging may result from not only loss of function in the individual organelles but also from the loss of their synergistic communication. Thus, there is a critical need to understand how mitochondrial-lysosomal communication adapts to stress and organellar dysfunction in aging. The central hypothesis of this proposal will be tested by the following specific aims: 1) Identify the stress signaling pathway connecting defective lysosomes and mitochondria, 2) Define the tissue-specific roles in lysosome-to- mitochondrial signaling in the aging model organism C. elegans, 3) Determine how lysosome-to-mitochondrial signaling changes during aging and Parkinson's disease and whether boosting this signaling can rescue health. This proposed application is innovative because 1) it focuses on the inter-organellar response of mitochondria and lysosomes to aging-related stress and 2) it will delineate mitochondrial-lysosomal communication in the multi-tissue aging organism C. elegans. Previous work in mitochondrial-lysosomal interactions used single-celled systems like yeast and cell culture which cannot fully model aging. The research proposed here is significant because by defining a novel route of communication between mitochondria and lysosomes required for cellular homeostasis in stress and aging, this proposal will provide strategies for therapeutic development to restore their communication during aging. In addition to the experimental research, this application also proposes a career development plan. Dr. Shen's career goal is to become an independent, academic investigator in aging science. Completing this proposal will allow her to establish a research niche in mitochondrial-lysosomal stress communication in aging and gain technical and leadership skills that are essential for her development into an independent investigator. To help her achieve her goals, Dr. Shen has assembled a Scientific Advisory Committee to deepen her understanding of lysosomal biology, RNA-seq, and metabolomics. This award will also give her the opportunity to improve her scientific writing, mentorship, and communication skills to support her transition into an independent investigator.

项目摘要/摘要 长期以来，衰老的健康状况下降与线粒体功能失调和溶酶体有关，但 这两个细胞器的失败是否连接不清楚。该应用程序的总体目标是 描述线粒体和溶酶体如何相互交流以促进衰老的健康。中央 假设是线粒体和溶酶体通常相互交流以促进健康，但是 在衰老期间，这会被妥协，导致两个细胞器共同发展为功能障碍。这是 由初步数据支持，表明有缺陷的溶酶体可以激活线粒体应力途径 年轻的成年秀丽隐杆线虫。理由是，在许多老化状况等帕金森氏病，都 线粒体和溶酶体有缺陷或具有家族突变。如果线粒体之间的通信 溶酶体很重要，随着衰老的衰老，健康下降可能不仅是由于个体的功能丧失而导致的 细胞器，而且由于失去了协同沟通。因此，迫切需要了解 线粒体 - 溶酶体沟通如何适应衰老中的压力和细胞器功能障碍。中央 该提案的假设将通过以下特定目的测试：1）确定应力信号通路 连接有缺陷的溶酶体和线粒体，2）定义组织特异性在溶酶体至 - 衰老模型有机体中的线粒体信号C.秀丽隐杆线虫，3）确定溶酶体对线粒体的方式 衰老和帕金森氏病期间的信号变化，以及增强这种信号是否可以挽救健康。 该提出的应用具有创新性，因为1）它重点介绍了线粒体的器官间响应 和与衰老相关的压力的溶酶体和2）它将描绘在线粒体 - 溶酶体通信中 多组织衰老有机体C.秀丽隐杆线虫。线粒体 - 溶酶体相互作用的先前工作使用了单细胞 酵母和细胞培养的系统无法完全模拟衰老。这里提出的研究很重要 因为通过定义细胞所需的线粒体和溶酶体之间的新型通信途径 在压力和衰老方面的体内平衡，该建议将为治疗发展提供策略，以恢复其 衰老期间的沟通。 除了实验研究外，该应用程序还提出了职业发展计划。 Shen博士 职业目标是成为老龄化科学领域的独立学术研究员。完成此建议将 让她在衰老中的线粒体散糖体压力交流中建立一个研究小众 对她发展成为独立调查员至关重要的技术和领导能力。提供帮助 她实现了自己的目标，Shen博士组建了一个科学咨询委员会，以加深她的理解 溶酶体生物学，RNA-SEQ和代谢组学。这个奖项还将使她有机会改善她 科学写作，指导和沟通技巧，以支持她向独立研究者的过渡。