Functional Consequences of Impaired Autophagy in Aging

衰老过程中自噬受损的功能后果

• 批准号: 9298507
• 负责人: ANA MARIA CUERVO
• 金额: $ 193.2万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298507
• 关键词: Address; Adipocytes; Adipose tissue; Advisory Committees; Affect; Age; Aging; Antigen Presentation Pathway; Area; Autophagocytosis; Biology of Aging; Brain; Cell physiology; Cells; Cellular biology; Characteristics; Chemicals; Chemistry; Communicable Diseases; Defect; Dementia; Dendritic Cells; Deterioration; Diabetes Mellitus; Diet; Disease; Elderly; Enhancers; Equilibrium; Experimental Models; Faculty; Failure; Goals; Health; Homeostasis; Human; Immune; Immune System Diseases; Immune System and Related Disorders; Immune response; Immune system; Immunologics; Immunology; Impaired cognition; Impairment; Intervention; Lead; Lipids; Liver; Longevity; Maintenance; Mammals; Mediating; Medical; Metabolic; Metabolic stress; Metabolic syndrome; Metabolism; Molecular; Neurons; Organ; Organelles; Organism; Pathway interactions; Pharmaceutical Chemistry; Pharmacology; Physiology; Play; Proteins; Proteome; Quality Control; Recycling; Research Activity; Resistance; Rodent; Role; Stress; System; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Therapeutic; Transcend; age related; aged; anti aging; cell growth regulation; cell injury; cognitive function; defined contribution; genotoxicity; group cooperation; immune function; immunosenescence; improved; insight; lipid metabolism; member; mouse model; novel; prevent; programs; proteotoxicity; public health relevance; response; restoration; stressor

DESCRIPTION (provided by applicant): This is the revised version of the first competing renewal of a Program Project (PP) focused on investigating the role that age-related changes in autophagy play in the functional alterations and inefficient response to immunological challenges and to stress of old organisms. Autophagy is a basic catabolic pathway essential for the maintenance of cellular homeostasis, regulation of the cellular energetic balance and an integral part of the response to stress. The components of the PP are four Projects involving 6 faculty members from 5 academic departments and three Cores that provide support to the research activities of the four projects. The projects share ideas, techniques and experimental models. Completion of aims requires participation of members from several of the projects. The PPG activities are reviewed periodically by a 6-member Scientific Advisory Committee. The long-term goal of the PP remains testing the overall hypothesis that impairment in autophagy mediates the functional deterioration and the inability to orchestrate an efficient response to stressors and to immunological challenges in old organisms. Building on the novel findings of the previous period, we propose now the following specific aims: 1) to characterize the involvement of different autophagic pathways, including endosomal-microautophagy (eMI), in the cellular response to stress with the focus now on proteotoxicity, lipotoxicity and genotoxicity in liver, brain (P1), adipose tissue (P4) and immune system (P2, P3); 2) to determine the impact of age-related changes in the different autophagic pathways on the immune response (P2, P3), adipose tissue homeostasis and remodeling (P4) and in the organismal resistance to stress (P1); 3) to analyze the effect of different interventions that modulate the activity of different autophagic pathways on the metabolic changes associated with aging (P1, P4) and on the failure of two essential immune functions, antigen processing and presentation (P2) and T cell activation (P3). These studies will require the synergistic cooperation of groups with expertise in autophagy, dendritic cell function, T cell biology, lipid metabolism, medicinal chemistry and oxidative cellular injury. Relevance: This PP explores the novel concepts that: 1. defective autophagic function is behind the higher vulnerability to stressors of old organisms and that 2. interventions aimed at restoring or enhancing autophagy could be implemented as anti-aging strategies to prolong health-span. Our studies may ultimately lead to fundamental insights in understanding, treating or preventing the metabolic alterations and declined cognitive and immune function of elders through manipulations of the autophagic system.

描述（由申请人提供）：这是项目（PP）的第一个竞争性更新的修订版本，重点是研究与年龄相关的自噬变化在功能改变以及对免疫挑战和旧有机体应激的低效反应中所起的作用。自噬是维持细胞稳态、调节细胞能量平衡和应激反应不可或缺的一部分的基本分解代谢途径。 PP 的组成部分包括四个项目，涉及来自 5 个学术部门的 6 名教员和三个核心，为这四个项目的研究活动提供支持。这些项目共享想法、技术和实验模型。目标的完成需要多个项目成员的参与。 PPG 的活动由 6 名成员组成的科学咨询委员会定期审查。 PP 的长期目标仍然是测试总体假设，即自噬损伤会介导旧有机体的功能恶化以及无法对压力源和免疫挑战做出有效反应。基于前一阶段的新发现，我们现在提出以下具体目标：1）描述不同自噬途径的参与，包括内体微自噬（eMI），在细胞对应激的反应中的参与，现在的重点是蛋白质毒性、脂毒性和基因毒性 在肝脏、大脑（P1）、脂肪组织（P4）和免疫系统（P2、P3）中； 2) 确定不同自噬途径中与年龄相关的变化对免疫反应（P2、P3）、脂肪组织稳态和重塑（P4）以及机体抗应激能力（P1）的影响； 3) 分析调节不同自噬途径活性的不同干预措施对与衰老相关的代谢变化（P1、P4）以及对抗原加工和呈递（P2）和T细胞激活（P3）这两种基本免疫功能失败的影响。这些研究需要具有专业知识的团体的协同合作 自噬、树突状细胞功能、T 细胞生物学、脂质代谢、药物化学和氧化细胞损伤。相关性：本 PP 探讨了以下新概念：1. 自噬功能缺陷是旧有机体更容易受到应激源影响的原因；2. 旨在恢复或增强自噬的干预措施可以作为抗衰老策略来实施，以延长健康寿命。我们的研究最终可能会通过操纵自噬系统，为理解、治疗或预防老年人的代谢改变以及认知和免疫功能下降提供基本见解。