Cell Non-Autonomous Regulation of NeuronalProteostasis

项目摘要 对内外应激源的反应能力对细胞的生存至关重要。 在一生中和在衰老过程中。尽管存在保护机制，但细胞损伤 在生物体的一生中积累，包括对蛋白质组的累积损伤。这样的赤字到 蛋白质动态平衡对神经元有特别有害的影响，在那里它们有助于 阿尔茨海默氏症等与年龄相关的神经退行性疾病的发展和进展 疾病。已经确定了对蛋白毒性作出反应的细胞内在机制；三个主要 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)在神经元和 其他类型的细胞，以缓解蛋白毒性应激。也有越来越多的证据表明，神经元健康 在这种情况下，非神经组织的通讯是调节的；然而，很少有 了解相关的潜在机制。 拟议工作的主要目标是描述细胞非自治的性质 以秀丽线虫为模型，研究神经元蛋白平衡的调控。首先，我们将确定如何 扰乱非神经性组织中的应激反应通路会影响神经元的蛋白稳定。近期 研究表明，激活三种蛋白质应激反应中的每一种都是神经元细胞中的非 自主保护外周组织免受蛋白质毒性；我们假设非自主的 保护也可能发生在相反的方向，即激活这些应激反应在 非神经元组织可以促进神经元蛋白平衡，这一点我们将在目标1中进行测试。 将更广泛地探索改变神经元的外周到神经元的通讯机制 蛋白质平衡。我们将识别细胞非自主调节神经元功能的基因。 在Aim 2中使用组织特异性基因敲除筛选方法进行蛋白质调控。 很可能有助于洞察组织间沟通影响的机制 神经元健康，并可能导致确定相关疾病的新治疗靶点 神经细胞蛋白毒性应激。 这项拟议工作的发起人安德鲁·迪林博士是蛋白质组学方面的著名专家 拥有出色的培训记录；他在加州大学伯克利分校的实验室代表着理想的环境 申请者需要发展研究、指导和沟通技能以成为 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.