Cell Non-Autonomous Regulation of NeuronalProteostasis

项目摘要 对内部和外部压力源的反应能力对细胞存活至关重要 在整个生命和衰老过程中。尽管存在保护机制， 在生物体的一生中，包括对蛋白质组的累积损伤。这种赤字， 蛋白质稳态在神经元中具有特别有害的影响，在那里它们有助于神经元的功能。 与年龄相关的神经退行性疾病的发展和进展，如阿尔茨海默氏症 疾病已经确定了响应蛋白毒性的细胞内在机制; 应激反应（细胞质热休克反应，内质网未折叠蛋白 反应和线粒体未折叠蛋白反应）在神经元中自主作用细胞， 其他细胞类型以改善蛋白毒性应激。还有越来越多的证据表明， 在这种情况下，通过来自非神经元组织的通信来调节;然而， 了解相关的潜在机制。 拟议工作的主要目标是表征细胞非自治的性质 调节神经元蛋白质稳态，使用C.优雅的模特首先，我们将确定如何 在非神经元组织中干扰应激反应途径影响神经元蛋白质稳态。最近 研究表明，在神经元细胞非- 自主保护外周组织免受蛋白毒性;我们假设非自主 保护也可能发生在相反的方向，即激活这些应激反应， 非神经元组织可以促进神经元蛋白质稳态，我们将在目的1中对此进行测试。二是 将更广泛地探索外周神经元之间的通讯机制， 蛋白质稳态我们将确定基因的功能细胞非自主调节神经元 Aim 2中使用组织特异性敲低筛选方法的蛋白质稳态。这些目标一起 很可能使我们深入了解组织间通讯影响 神经元健康，并可能导致确定新的治疗目标的疾病相关 神经元蛋白毒性应激。 这项工作的发起人安德鲁·迪林博士是一位著名的蛋白质抑制专家 具有良好的培训记录;他在加州大学伯克利分校的实验室代表了理想的环境， 申请人发展必要的研究，指导和沟通技巧，成为一个 独立调查员

Project Summary The capacity to response to internal and external stressors is critical for cellular survival throughout life and during aging. Despite the presence of protective mechanisms, cellular damage accrues over an organism’s lifetime, including accumulated damage to the proteome. Such deficits to protein homeostasis have a particularly deleterious effect in neurons, where they contribute to the development and progression of age-associated neurodegenerative diseases, such as Alzheimer’s disease. Cell-intrinsic mechanisms for responding to proteotoxicity have been identified; three major stress responses (the cytoplasmic heat shock response, the endoplasmic reticulum unfolded protein response, and the mitochondrial unfolded protein response) act cell autonomously in neurons and other cell types to ameliorate proteotoxic stress. There is also mounting evidence that neuronal health in this context is modulated by communication from non-neuronal tissues; however, very little is known about the relevant underlying mechanisms. The major objective of the proposed work is to characterize the nature of cell non-autonomous regulation of neuronal proteostasis, using C. elegans as a model. First, we will determine how perturbing stress response pathways in non-neuronal tissues affect neuronal proteostasis. Recent work has shown that activation of each of the three proteostatic stress responses in neurons cell non- autonomously protects peripheral tissues from proteotoxicity; we hypothesize that non-autonomous protection might also occur in the reverse direction, i.e. that activation of these stress responses in non-neuronal tissues can promote neuronal proteostasis, which we will test by in Aim 1. Second, we will more broadly explore mechanisms of periphery-to-neuron communication that alter neuronal proteostasis. We will identify genes that function cell non-autonomously to regulate neuronal proteostasis using a tissue-specific knockdown screening approach in Aim 2. Together these aims are likely to yield insight into the mechanisms by which inter-tissue communication influences neuronal health and could lead to the identification of new therapeutic targets for diseases associated with neuronal proteotoxic stress. The sponsor for the proposed work, Dr. Andrew Dillin, is a renowned expert in proteostasis with an excellent training record; his laboratory at UC Berkeley represents an ideal environment for the applicant to develop the research, mentorship, and communication skills necessary to become an independent investigator.