Functional Consequences of Impaired Autophagy in Aging

这是一个新的计划项目，旨在研究自噬中与年龄相关的变化在功能改变和对免疫挑战和旧生物体压力的无效反应中所起的作用。提出了四个项目，涉及3个学术部门的4名教师。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若干项目的成员的参与。 溶酶体中细胞内组分的降解或自噬对于细胞内稳态是必不可少的，作为营养物稀少和响应压力时的能量来源。自噬的两个最好的特征类型，大自噬和分子伴侣介导的自噬的活性，在旧的生物体中被改变。我们推测，这种自噬损伤可能是老年机体功能退化和无法应对免疫挑战和压力的原因。为了验证这一假设，我们将：1）表征肝脏中不同自噬途径的参与（项目1和4），大脑（P1）和免疫系统（P2和P3）分析这些器官自噬系统随年龄的变化（P1-4）;和3）确定这些变化对衰老代谢综合征（P4）、认知功能的逐渐恶化（P1）和两种基本免疫功能随年龄的衰竭的贡献，抗原加工和呈递（P2）和T辅助细胞活化和耐受（P3）。这些研究将需要具有自噬、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（核心B）提供最先进的显微镜和成像服务，衰老和转基因动物核心（核心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的相关领域。每个拟议项目都是独立调查人员之间的协作努力，将他们的个人专门知识扩展到否则无法有效调查的领域。这四个小组一直在共同努力，并将协同互动。 重要性：这些研究可能最终导致理解，治疗或预防老年人代谢改变和认知和免疫功能下降的基本见解。

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.