Functional Consequences of Impaired Autophagy in Aging

描述(由申请人提供)：这是一个新的计划项目，旨在调查自噬中与年龄相关的变化在免疫挑战和应激的免疫挑战和压力的低效反应中所起的作用。提出了四个项目，涉及来自3个学术部门的4名教职员工。这些项目将分享想法、技术和实验模型。完成最具体的目标需要来自几个项目的成员的参与。溶酶体中细胞内成分的降解，或自噬，是细胞动态平衡的关键，在营养稀少和应对压力时，它是一种能量来源。在老年生物体中，两种最具特征的自噬类型--巨型自噬和伴侣介导的自噬--的活性发生了变化。我们推测，自噬的这种损害可能是老生物体功能恶化和对免疫挑战和应激反应能力下降的原因。为了验证这一假说，我们将：1)表征在基础或应激条件下，肝脏(项目1和4)、脑(P1)和免疫系统(P2和3)中不同的自噬途径的参与；2)分析这些器官(P1-4)中自噬系统随年龄的变化；以及3)确定这些变化对衰老(P4)的代谢综合征(P4)、认知功能的逐渐恶化(P1)以及两种基本免疫功能--抗原处理和呈递(P2)和辅助性T细胞激活和耐受(P3)--随年龄的丧失的贡献。这些研究将需要在自噬、树突状细胞功能、T细胞生物学、脂肪性肝病、脂肪代谢和氧化细胞损伤方面的专家小组的协同合作。该计划包括三个核心：行政核心(核心A)提供必要的秘书和簿记功能；分析成像核心(核心B)提供最先进的显微镜和成像服务，以及老化和转基因动物核心(核心C)提供本项目所需的转基因和老龄小鼠群体的维护、育种和基因分型。所有四个项目都涉及细胞新陈代谢、分子和细胞免疫学以及衰老生物学等相互关联的领域。每个拟议的项目都是独立调查人员之间的合作努力，将把他们的个人专门知识扩展到原本无法有效调查的领域。这四个小组一直在合作，并将协同互动。意义：这些研究最终可能为理解、治疗或预防老年人特有的代谢改变和认知和免疫功能下降带来基本的见解。

DESCRIPTION (provided by applicant): This is a new Program Project to investigate 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. Four Projects involving 4 faculty members from 3 academic departments are proposed. These projects will share ideas, techniques and experimental models. Completion of most specific aims requires the participation of members from several of the projects. Degradation of intracellular components in lysosomes, or autophagy, is essential for cellular homeostasis, as an energy source when nutrients are sparse and in response to stress. The activity of the two best characterized types of autophagy, macroautophagy and chaperone-mediated autophagy, is altered in old organisms. We hypothesize that this impairment in autophagy could be behind the functional deterioration and the inability to respond to immunological challenges and to stress in old organism. To test this hypothesis we will: 1) characterize the involvement of different autophagic pathways in liver (Project 1 and 4), brain (P1) and the immune system (P2 and 3), under basal or stress conditions; 2) analyze the changes with age in the autophagic system in these organs (P1-4); and 3) determine the contribution of these changes to the metabolic syndrome of aging (P4), the gradual deterioration of cognitive function (P1) and to the failure with age of two essential immune functions, antigen processing and presentation (P2) and T helper cell activation and tolerance (P3). These studies will require the synergistic cooperation of groups with expertise in autophagy, dendritic cell function, T cell biology, steatotic liver disease, lipid metabolism and oxidative cellular injury. This Program includes three Cores: the Administrative Core (Core A) provides the necessary secretarial and bookkeeping functions; the Analytical Imaging Core (Core B) provides state-of-the-art microscopy and imaging services, and the Aging and Transgenic Animal Core (Core C) provides maintenance, breeding and genotyping of the transgenic and aging mouse colonies required for this project. All four Projects are concerned with interrelated areas of cellular metabolism, molecular and cellular immunology and the biology of aging. Each proposed project represents collaborative efforts between independent investigators that will extend their individual expertise into areas that could not otherwise be effectively investigated. The four groups have been working together and will interact synergistically. Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders.