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.

抽象的 该计划项目拨款 (PPG) 申请的总体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。 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了解将有助于解决这一问题。 揭示溶酶体对阿尔茨海默病的重要机制见解和新的治疗靶点。 在蛋白质聚集体的清除中发挥着关键作用，而蛋白质聚集体的功能会随着年龄的增长而下降。 溶酶体功能可以促进健康衰老并对抗与年龄相关的病理性蛋白质积累。 虽然溶酶体传统上被认为是最终降解的被动细胞器，但新兴的 包括我们的 PPG 研究人员所做的开创性工作在内的证据表明，溶酶体是 多个细胞过程的积极参与者，包括应激反应、营养感应和细胞 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传导。 我们提出了三个创新研究项目，旨在阐明溶酶体到细胞核的信号传导 衰老和疾病中调节溶酶体稳态的途径，重点关注 tau 发病机制。 研究是通过我们为这项工作创建的几个强大的实验工具以及最新的 我们提出的蛋白质组学和代谢组学核心提供的艺术技术将具有持久性。 首先，我们解决了理解溶酶体生物学的关键障碍。 衰老和AD，特别是在病理性tau蛋白的背景下，它越来越被认为是一种关键疾病—— 其次，我们的研究有望干预 AD 和其他蛋白质聚集体。 通过揭示分子途径来利用先天溶酶体传感机制和 第三，我们的工作将产生一流的衰老和 Tau 病相关溶酶体。 小鼠皮质和海马的溶酶体蛋白质组和代谢组图谱（ATLas）将被共享 通过基于网络的开放获取平台，这将广泛支持我们 PPG 之外的研究来理解。 溶酶体在衰老、阿尔茨海默病和 总体而言，我们的 PPG 远大于各个部分的总和。 PPG 研究人员之间具有互补的专业知识和密切的互动， 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 ATL 可以与整个研究界共享。