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，旨在研究年龄相关的自噬变化在衰老生物体对免疫挑战和应激的功能改变和低效反应中的作用。提出了4个项目，涉及3个学系的4名教员。这些项目将分享想法、技术和实验模型。大多数具体目标的完成需要来自多个项目的成员的参与。溶酶体中细胞内成分的降解或自噬对细胞稳态至关重要，在营养物质匮乏和应激反应中作为能量来源。两种最具特征的自噬类型，巨噬和伴侣介导的自噬，在年老的生物体中发生了改变。我们假设这种自噬损伤可能是老年机体功能恶化和对免疫挑战和应激反应能力下降的原因。为了验证这一假设，我们将：1)描述在基础或应激条件下，肝脏（项目1和4）、大脑（项目P1）和免疫系统（项目P2和3）中不同自噬途径的参与；2)分析这些器官自噬系统随年龄的变化（P1-4）；3)确定这些变化对衰老代谢综合征（P4）、认知功能逐渐退化（P1）以及两种基本免疫功能（抗原加工和递呈（P2）和T辅助细胞激活和耐受（P3））随着年龄的增长而失效的贡献。这些研究将需要在自噬、树突状细胞功能、T细胞生物学、脂肪变性肝病、脂质代谢和氧化细胞损伤方面具有专业知识的小组的协同合作。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（Core B）提供最先进的显微镜和成像服务，老化和转基因动物核心（Core C）提供本项目所需的转基因和衰老小鼠菌落的维护、育种和基因分型。所有四个项目都涉及细胞代谢、分子和细胞免疫学以及衰老生物学等相互关联的领域。每一个拟议的项目都代表着独立调查人员之间的合作努力，将他们的个人专业知识扩展到否则无法有效调查的领域。这四个小组一直在一起工作，并将发挥协同作用。意义：这些研究可能最终为理解、治疗或预防老年人代谢改变、认知和免疫功能下降的特征提供根本性的见解。

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.