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: 10191587
• 负责人: Koning Shen
• 金额: $ 11.33万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191587
• 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.

项目总结/摘要 长期以来，衰老中健康状况的下降与线粒体和溶酶体功能障碍有关，但 这两种细胞器的失效是否有联系尚不清楚。此应用程序的总体目标是 描绘线粒体和溶酶体如何相互沟通，以促进衰老中的健康。中央 假设是线粒体和溶酶体通常相互交流以促进健康，但 这在衰老过程中变得妥协，导致两个细胞器共同退化成功能障碍。这是 初步数据显示，有缺陷的溶酶体可以激活线粒体应激途径， 青少年C.优美的其基本原理是，在许多衰老的条件下，如帕金森氏病， 线粒体和溶酶体是有缺陷的或具有家族性突变。如果线粒体之间的通讯 和溶酶体是重要的，随着年龄的增长，健康下降可能不仅是由于个人功能的丧失， 细胞器，但也从他们的协同通信的损失。因此，我们迫切需要了解 细胞-溶酶体通讯如何适应衰老中的应激和细胞器功能障碍。中央 本研究将通过以下几个具体目标来验证这一假设：1）确定应激信号通路 连接缺陷的溶酶体和线粒体，2）定义组织特异性的作用，在溶酶体- 衰老模型生物体中的线粒体信号传导C. 3）确定溶酶体如何与线粒体结合， 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拯救健康。 这项拟议的应用具有创新性，因为1）它关注线粒体的细胞器间反应 和溶酶体对衰老相关应激的反应; 2）它将描绘衰老相关应激中的神经元-溶酶体通讯， 多组织衰老生物C.优美的以前的工作中使用的单细胞溶酶体相互作用 酵母和细胞培养等系统无法完全模拟衰老。这里提出的研究是有意义的 因为通过定义线粒体和溶酶体之间的新的通讯途径， 内稳态的压力和老化，这一建议将提供战略的治疗发展，以恢复他们的 老化期间的沟通。 除了实验研究之外，本申请还提出了职业发展计划。沈医生的 职业目标是成为一个独立的，学术研究老化科学。完成本提案将 使她能够在衰老和增益中的脑-溶酶体应激通信方面建立一个研究利基 技术和领导技能是她发展成为独立调查员所必需的。帮助 为了实现她目标，沈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测序和代谢组学。这个奖项也将给她机会，以提高她的 科学写作，指导和沟通技巧，以支持她过渡到一个独立的调查。