Lysosome Regulation and Signaling in Aging and Alzheimer's Disease

衰老和阿尔茨海默病中的溶酶体调节和信号传导

• 批准号: 10614231
• 负责人: Hui Zheng
• 金额: $ 8.51万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614231
• 关键词: Address; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Applications Grants; Atlases; Automobile Driving; Biological Process; Biological Response Modifier Therapy; Biology; Biology of Aging; Cell Nucleus; Cell physiology; Communities; Disease; Etiology; Goals; Hippocampus (Brain); Homeostasis; Intervention; Lysosomes; Metabolism; Molecular; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Online Systems; Organelles; Participant; Pathogenesis; Pathologic; Pathology; Pathway interactions; Play; Program Research Project Grants; Proteins; Proteome; Proteomics; Regulation; Research; Research Personnel; Research Project Grants; Research Support; Risk Factors; Role; Signal Pathway; Signal Transduction; Sum; Tauopathies; Technology; Work; biological adaptation to stress; brain health; combat; detection of nutrient; healthy aging; innovation; insight; metabolome; metabolomics; multidisciplinary; new therapeutic target; novel; protein aggregation; tau Proteins; therapeutic target; tool

Abstract The overarching goal of this Program Project Grant (PPG) application is to investigate signaling pathways regulating lysosomal homoeostasis in aging and Alzheimer’s disease (AD). Although the etiology of AD remains elusive, age is the greatest risk factor. Therefore, an advanced understanding of aging biology will reveal crucial mechanistic insights and novel therapeutic targets for Alzheimer’s disease. The lysosome plays a critical role in the clearance of protein aggregates whose function declines with aging. Thus enhancing lysosomal function may promote healthy aging and combat age-associated pathological protein accumulation. While the lysosome has been traditionally regarded as a passive organelle for terminal degradation, emerging evidence including the groundbreaking work done by our PPG investigators, demonstrates that the lysosome is an active participant in multiple cellular processes, including stress responses, nutrient sensing, and cellular metabolism. Each of these functions involve coordinated signaling between the lysosome and the nucleus. We propose three innovative research projects aimed at elucidating the lysosome-to-nucleus signaling pathways that regulate lysosomal homeostasis in aging and disease, with a focus on tau pathogenesis. Our studies are enabled by several powerful experimental tools we have created for this work, and by state-of-the- art technologies offered by our proposed proteomics and metabolomics cores. Our PPG will have a lasting impact on the field in several ways. First, we address critical barriers to understanding lysosomal biology in aging and AD, particularly in the context of pathological tau which is increasingly recognized as a key disease- driving factor in AD. Second, our study holds promise for intervention in AD and other protein aggregate pathologies by uncovering molecular pathways to harness innate lysosomal sensing mechanisms and clearance capacity. Third, our work will produce a first-in-class Aging- and Tauopathy-associated Lysosomal atlas (ATLas) of the lysosomal proteome and metabolome from mouse cortex and hippocampus to be shared through a web-based open-access platform. This will broadly support research beyond our PPG to understand the biological function and therapeutic targeting of the lysosome in aging, Alzheimer’s disease and neurodegeneration. Overall, our PPG is substantially greater than the sum of its parts through the complementary expertise and close interactions among the PPG investigators, the coherent and multidisciplinary nature of the research projects, the powerful technical platforms offered by the cores, and the valuable ATLas to be shared to the research community at large.

摘要 该计划项目拨款(PPG)应用程序的首要目标是研究信号通路 调节衰老和阿尔茨海默病(AD)中的溶酶体稳态。虽然阿尔茨海默病的病因 仍然难以捉摸，年龄是最大的风险因素。因此，对衰老生物学的深入理解将 揭示阿尔茨海默病的关键机制洞察力和新的治疗目标。溶酶体演奏 在清除蛋白质聚集体中的关键作用，这些聚集体的功能随着年龄的增长而下降。从而增强了 溶酶体功能可能促进健康衰老，对抗与年龄相关的病理性蛋白积聚。 虽然溶酶体传统上被认为是末端降解的被动细胞器，但出现了 包括我们的PPG调查人员所做的开创性工作在内的证据表明，溶酶体是 积极参与多种细胞过程，包括应激反应、营养感知和细胞 新陈代谢。这些功能中的每一个都涉及溶酶体和细胞核之间的协调信号。 我们提出了三个创新性的研究项目，旨在阐明溶酶体到细胞核的信号转导 在衰老和疾病中调节溶酶体动态平衡的途径，重点是tau的发病机制。我们的 研究是由我们为这项工作创造的几个强大的实验工具和最新的- 我们建议的蛋白质组学和代谢组学核心提供的ART技术。我们的PPG将会有一个持久的 在几个方面对该领域产生了影响。首先，我们解决了理解溶酶体生物学的关键障碍 衰老和阿尔茨海默病，特别是在病理性tau的背景下，这种疾病越来越被认为是一种关键疾病- AD的驱动因素。其次，我们的研究有望对AD和其他蛋白质聚集体进行干预 通过揭示分子通路来利用溶酶体固有的感知机制和 通关能力。第三，我们的工作将产生一流的与衰老和肌萎缩症相关的溶酶体 小鼠大脑皮层和海马区溶酶体蛋白质组和代谢组图谱共享 通过一个基于网络的开放获取平台。这将在很大程度上支持我们PPG以外的研究 溶酶体在衰老、阿尔茨海默病和老年性痴呆中的生物学功能和治疗靶点 神经退行性变。总体而言，我们的PPG远远大于其各部分的总和 PPG调查员之间的专业知识互补和密切互动 研究项目的多学科性质，核心提供的强大技术平台，以及 有价值的地图集将分享给广大研究界。