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.

项目概要/摘要 长期以来，衰老导致的健康状况下降与线粒体和溶酶体功能失调有关，但 这两种细胞器的故障是否存在关联仍不清楚。该应用程序的总体目标是 描述线粒体和溶酶体如何相互沟通以促进衰老过程中的健康。中央 假设线粒体和溶酶体通常相互沟通以促进健康，但是 这在衰老过程中会受到损害，导致这两个细胞器共同退化为功能障碍。这是 初步数据表明，有缺陷的溶酶体可以激活线粒体应激途径 年轻的成年秀丽隐杆线虫。其基本原理是，在帕金森病等许多衰老疾病中，两者 线粒体和溶酶体有缺陷或有家族突变。如果线粒体之间有通讯 溶酶体很重要，随着年龄的增长，健康状况下降可能不仅是由于个体功能丧失造成的 细胞器还因失去协同通讯而受到影响。因此，迫切需要了解 线粒体-溶酶体通讯如何适应衰老过程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具体目标进行检验：1）确定压力信号传导途径 连接有缺陷的溶酶体和线粒体，2) 定义溶酶体与线粒体之间的组织特异性作用 衰老模型生物线虫中的线粒体信号传导，3) 确定溶酶体与线粒体之间的相互作用 衰老和帕金森病期间的信号变化以及增强这种信号是否可以挽救健康。 这一提出的应用具有创新性，因为 1) 它专注于线粒体的细胞器间反应 和溶酶体与衰老相关的压力，2）它将描绘线粒体-溶酶体的通讯 多组织衰老生物线虫。先前的线粒体-溶酶体相互作用研究使用单细胞 酵母和细胞培养等系统无法完全模拟衰老。这里提出的研究意义重大 因为通过定义细胞所需的线粒体和溶酶体之间的新通讯途径 压力和衰老中的稳态，该提案将为治疗开发提供策略，以恢复其 衰老过程中的沟通。 除了实验研究之外，本申请还提出了职业发展计划。沉博士的 职业目标是成为衰老科学领域的独立学术研究者。完成本提案将 让她能够在衰老和增重过程中线粒体-溶酶体压力通讯方面建立一个研究领域 技术和领导技能对于她发展成为一名独立调查员至关重要。帮助 为了实现她的目标，沉博士组建了一个科学顾问委员会来加深她的理解 溶酶体生物学、RNA-seq 和代谢组学。这个奖项也将给她一个提升自己的机会 科学写作、指导和沟通技巧支持她转变为独立研究者。