Mechanism of organelle dysfunction during aging and the related rejuvenation process

衰老过程中细胞器功能障碍的机制及相关的返老还童过程

• 批准号: 10239073
• 负责人: Chuankai Zhou
• 金额: $ 48.5万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239073
• 关键词: ATP Synthesis Pathway; Address; Affect; Age; Aging; Autophagocytosis; Binding; Binding Proteins; Biochemical; Biochemistry; Biological; Biological Assay; Biological Models; Biology of Aging; Cell physiology; Cells; Cellular biology; Data; Daughter; Defect; Deterioration; Disease; Ensure; Functional disorder; Future; Gene Expression Profiling; Genetic; Goals; Health; Human Pathology; Image; Imaging technology; Impairment; In Vitro; Intervention; Knowledge; Malignant Neoplasms; Metabolic; Metabolism; Methods; Mission; Mitochondria; Mitochondrial Proteins; Modeling; Molecular Chaperones; Mothers; Neurodegenerative Disorders; Newborn Infant; Organelles; Outcome; Peptide Signal Sequences; Physiological; Process; Protein Conformation; Protein Sortings; Proteins; Proteome; Proteomics; Reaction; Rejuvenation; Research; Respiration; Risk Factors; Saccharomycetales; Signal Transduction; Surface; System; Technology; Testing; Tissues; Ubiquitin; Work; acute stress; age related; aged; cell age; daughter cell; frontier; imaging approach; improved; in vivo; induced pluripotent stem cell; macromolecule; metabolomics; misfolded protein; mitochondrial dysfunction; mitochondrial metabolism; multicatalytic endopeptidase complex; protein aggregation; protein degradation; protein folding; protein protein interaction; proteostasis; receptor; repaired; response

ABSTRACT   Aging is a general physiological deterioration that constitutes the primary risk factor for major human pathologies, including cancer and neurodegenerative diseases. Research to develop cures for these diseases has been hampered because we lack a clear understanding of the factors that underlie the aging contribution. Elucidating these factors remains an important frontier in aging research and will accelerate our ability to intervene in aging-related diseases. Among these factors, loss of protein homeostasis (proteostasis) and the consequent accumulation of aggregated proteins represent a major hallmark of aging. Proteostasis is the guardian of the proteome to ensure proper protein folding, protein-protein interaction, and consequently the organization of the macromolecules and organelles within a cell. Although proteostasis dysfunction during aging has been explored in the context of protein aggregation, a largely unknown consequence of proteostasis dysfunction is the alteration of organelle composition and function. Of relevance to this question, cytosolic protein aggregates formed upon proteostasis defects are anchored on the surface of mitochondria, which allows mitochondria to import these aggregated cytosolic proteins. The goals of this work are to 1) understand how proteostasis defects and aging affect the integrity of mitochondria and other organelles, 2) investigate how proteostasis defects regulate mitochondrial metabolism, and 3) explore mechanisms to rejuvenate the age- related mitochondrial dysfunction and proteostasis defects. These Aims will be accomplished by using an integration of cutting-edge imaging, proteomics, metabolomics, and biochemical technologies to interrogate related questions in budding yeast, a well-characterized model system for cell biology and aging research. This work will advance our understanding of aging and age-related diseases that are featured with proteostasis defects and mitochondrial dysfunction, while establishing the basis for future explorations in the rejuvenation of aged cells and the interventions for age-related diseases.

摘要   衰老是一种普遍的生理恶化，构成了人类主要疾病的主要危险因素。 病理学，包括癌症和神经退行性疾病。研究开发这些疾病的治疗方法 一直受到阻碍，因为我们缺乏对老龄化贡献的基础因素的清晰理解。 阐明这些因素仍然是老龄化研究的一个重要前沿，并将加速我们的能力， 干预与衰老有关的疾病。在这些因素中，蛋白质稳态（蛋白质稳态）的丧失和 随后聚集蛋白的积累代表了衰老的主要标志。蛋白质稳态是 蛋白质组的监护人，以确保正确的蛋白质折叠，蛋白质-蛋白质相互作用，从而 细胞内大分子和细胞器的组织。虽然衰老过程中蛋白质稳态功能障碍 已经在蛋白质聚集的背景下进行了探索，这是蛋白质稳定的一个很大程度上未知的结果 功能障碍是细胞器组成和功能的改变。与此相关的是，胞浆蛋白 在蛋白质稳态缺陷时形成的聚集体锚定在线粒体的表面上， 线粒体来输入这些聚集的胞质蛋白。这项工作的目标是1）了解如何 蛋白质稳态缺陷和衰老影响线粒体和其他细胞器的完整性，2）研究如何 蛋白质稳态缺陷调节线粒体代谢，3）探索返老还童的机制- 相关的线粒体功能障碍和蛋白质稳态缺陷。这些目标将通过使用 整合尖端成像、蛋白质组学、代谢组学和生化技术， 芽殖酵母的相关问题，细胞生物学和衰老研究的良好表征模型系统。这 这项工作将促进我们对以蛋白质稳态为特征的衰老和与年龄相关的疾病的理解 缺陷和线粒体功能障碍，同时为未来的复兴探索奠定基础， 衰老细胞和与年龄有关的疾病的干预措施。