TFEB-mediated lysosome-to-nucleus signaling in aging and lifespan regulation

TFEB 介导的溶酶体到细胞核信号传导在衰老和寿命调节中的作用

• 批准号: 10172235
• 负责人: Marco Sardiello
• 金额: $ 55.83万
• 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/10172235
• 关键词: Affect; Age; Age Factors; Aging; Alzheimer' s Disease; Atlases; Attenuated; Autophagocytosis; Brain; Cardiovascular Diseases; Cell Nucleus; Cells; Chromatin; Chromatin Remodeling Factor; Clinical Treatment; Data; Degradation Pathway; Dependence; Development; Elderly; Enzymes; Foundations; Future; Genes; Genetic Transcription; Goals; Health; Healthcare; Histones; Homeostasis; Impairment; Individual; Investigation; Knock-in; Link; Longevity; Lysosomes; Malignant Neoplasms; Maps; Mediating; Metabolic; Metabolism; Modernization; Molecular Target; Morbidity - disease rate; Mus; Nerve Degeneration; Neurons; Organ; Organelles; Organism; Pathway interactions; Pattern; Phenotype; Population; Post-Translational Protein Processing; Predisposition; Proteome; Proteomics; Regulation; SIRT1 gene; Signal Pathway; Signal Transduction; Tauopathies; Testing; Tissues; Transducers; Work; age related; age related neurodegeneration; aging brain; base; brain tissue; cellular targeting; clinical investigation; conditional knockout; design and construction; exhaust; frailty; genome-wide; healthspan; knowledge of results; macromolecule; male; metabolome; programs; protein aggregation; senescence; sex; synergism; therapy development; tool; transcription factor

Abstract Aging is characterized by the progressive inability of cells, tissues, and organs to maintain their functional integrity and is accompanied by an increased susceptibility to morbidity—the odds to develop neurodegeneration, cancer, or cardiovascular disease increase continuously with age. There is currently no general, actionable strategy to slow down dysregulation of cell and tissue homeostasis in the aging organism. As a result, advances in healthcare in the modern era have paradoxically increased frailty and morbidity among the elderly by increasing lifespan without significantly impacting on age-related homeostasis dysregulation. Owing to a continuously aging world population, there is therefore an urgent and unmet need to identify actionable cellular and molecular targets for the development of treatments aimed at increasing healthspan along with lifespan. Hallmarks of aging are a decline in lysosome-mediated degradation pathways and chromatin dysregulation. This proposal focuses on a transcription factor EB-mediated lysosome-to-nucleus signaling pathway, the modulation of which extends mouse lifespan by 30% in males. We will systematically and mechanistically investigate the three components of this signaling pathway—namely the lysosome, the signaling transducers, and chromatin regulators—during aging by leveraging unique tools that we have developed to study lysosomal content and signaling components. Results from this study will provide the first age-associated atlas of the lysosomal content in the mammalian brain and will pioneer the investigation of lysosome-to-nucleus signaling in aging. Knowledge resulting from this study could lay the foundation for future translational investigations of clinical treatment of aging and age-related neurodegenerative disease.

抽象的 衰老的特征是细胞，组织和器官保持其功能 正直，是通过增加发病率的敏感性来实现的 - 发展的可能性 神经变性，癌症或心血管疾病随着年龄的增长不断增加。目前没有 一般，可行的策略，以减慢老化组织中细胞和组织稳态失调的失调。 结果，现代医疗保健的进步在频繁地增加了脆弱和发病率 在较早的寿命中，没有显着影响与年龄有关的体内稳态 失调。由于世界持续衰老的人口，因此有紧急且未满足的需求 确定可行的细胞和分子靶标，以开发旨在增加的治疗 HealthSpan以及寿命。衰老的标志是溶酶体介导的降解途径的下降 和染色质失调。该建议重点介绍转录因子EB介导的溶酶体至核子 信号通路，其调制的男性将小鼠寿命延长了30％。我们将系统地 并机械地研究了该信号通路的三个组成部分，即溶酶体 信号传感器和染色质调节剂 - 通过利用我们拥有的独特工具来衰老 开发用于研究溶酶体含量和信号传导成分。这项研究的结果将提供第一个 与哺乳动物大脑中溶酶体含量相关的年龄相关地图集，并将先驱 衰老中的溶酶体对核心信号传导。这项研究产生的知识可能为未来奠定基础 衰老和与年龄相关的神经退行性疾病的临床治疗的翻译研究。