Stress Response Mechanisms Regulating Neuronal Health in the Mammalian Central Nervous System.

调节哺乳动物中枢神经系统神经元健康的应激反应机制。

• 批准号: 10729206
• 负责人: Caitlin Marie Seluzicki
• 金额: $ 4.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10729206
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Area; Biochemical; Biological; Brain Diseases; Cell physiology; Cells; Cellular Stress; Central Nervous System; Cerebellar Ataxia; Cognitive; Cognitive deficits; Curiosities; Data; Development; Disease; Disease Progression; Down-Regulation; Elderly; Endowment; Event; Genes; Genetic; Genetic Diseases; Genetic Screening; Health; Heat Stress Disorders; Heat-Shock Response; Hippocampus; Hour; Human; Impaired cognition; Individual; Inflammatory; Investigation; Laboratory Finding; Lysosomes; Measurement; Measures; Mediating; Mentors; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Neurons; Onset of illness; Outcome; Pathology; Pathway interactions; Patients; Phase; Physiological; Polyribosomes; Predisposition; Proteins; Recovery; Regulation; Research; Research Personnel; Ribosomal RNA; Ribosomes; Role; Stress; System; Temperature; Testing; Tissues; Training; Transcript; Translating; Translational Regulation; Translations; Up-Regulation; Work; age related; biological adaptation to stress; brain health; career; disorder risk; early onset; environmental stressor; human disease; in vivo; insight; interest; molecular targeted therapies; motor deficit; mouse model; neuronal survival; novel; pre-doctoral; programs; protein degradation; proteostasis; response; ribosome profiling; skill acquisition; stress resilience; stressor; therapeutic target; transcription factor; transcriptome sequencing

PROJECT SUMMARY Every human being is endowed with a finite number of neurons that must endure a lifetime of environmental stressors. This proposal focuses on studying a neuronal stress response and recovery mechanism with relevance to neuronal function and survival. These studies are directly applicable to human disease, aging, and external impacts of neuronal health. Briefly, we have found that neuronal cells respond to heat stress in a non- canonical way, by downregulating translation. This is rapidly recoverable when returned to baseline conditions within a finite window, beyond which point the cells die. We also discovered that stress response factors were being activated during recovery and are important for neuronal cell function. Based on these and other original findings during the predoctoral phase, our central hypothesis is that neurons endure heat stress in part through translational reprogramming to prepare the system for survival in the event that recovery is an option. Testing this hypothesis, we discovered neurons upregulate Hsp70 in order to survive this recovery phase. Intriguingly, upregulation of Hsp70 has been shown to be relevant to a variety of neurodegenerative disorders, including Alzheimer’s disease. The rationale for the proposed research during the F99 phase is that the molecular programs that mediate neuronal function and survival during heat stress are poorly understood and further understanding will provide critical insight into the underlying causes of stressors that impact the human nervous system in health and disease. Given the critical importance of neuronal stress response to human health, the long-range objective of the proposed research is to understand the role of dysfunctional stress response in neurodegeneration and how it contributes to decreased neuronal stress resilience and inability to recover from stress. We will do this through biochemical, molecular, cellular and physiological measurement to characterize stress response in neuronal cells and molecular mechanisms essential for recovery. Specifically: Aim 1. To investigate the mechanism of stress induced translation regulation and recovery, to test our hypothesis that heat stress induced translation reprogramming is vital to prepare the system for potential recovery and is a key feature in neuronal health and survival; Aim 2. To study disrupted proteostasis in purkinje neurons of a cerebellar ataxia mouse model, to test my hypothesis that mutations resulting in the loss of RREB1 alters protein degradation, which may participate in the observed neurodegeneration and make cells more susceptible to cellular stress. The completed predoctoral and proposed F99 studies create a rigorous program for studying neuronal stress response that will be applied to the proposed K00 studies. The proposed K00 studies will identify factors that lead to more rapid onset or progressive neurodegenerative disease, as well as factors that disallow neuronal recovery from stress. Findings from the K00 hold promise for generating therapeutic targets to extend cognitive well-span and promote neuronal recovery from stress.

项目概要 每个人都被赋予了有限数量的神经元，这些神经元必须在一生中承受环境的影响。 压力源。该提案重点研究神经元应激反应和恢复机制 与神经元功能和存活的相关性。这些研究直接适用于人类疾病、衰老和 神经元健康的外部影响。简而言之，我们发现神经元细胞在非 规范的方式，通过下调翻译。当返回到基线条件时，这可以快速恢复 在有限的窗口内，超过该窗口细胞就会死亡。我们还发现压力反应因素 在恢复过程中被激活，对神经细胞功能很重要。基于这些和其他原创 在博士前阶段的研究结果中，我们的中心假设是神经元承受热应激的部分原因是 翻译重编程，以使系统在可以选择恢复的情况下为生存做好准备。测试 根据这个假设，我们发现神经元上调 Hsp70 以度过这个恢复阶段。有趣的是， Hsp70 的上调已被证明与多种神经退行性疾病相关，包括 阿尔茨海默病。 F99 阶段拟议研究的基本原理是，分子 热应激期间介导神经元功能和生存的程序知之甚少，并且进一步 理解将为影响人类神经的压力源的根本原因提供重要的见解 健康和疾病系统。鉴于神经元应激反应对人类健康至关重要， 拟议研究的长期目标是了解功能失调的应激反应在 神经退行性变以及它如何导致神经元应激恢复能力下降和无法恢复 压力。我们将通过生化、分子、细胞和生理测量来表征 神经元细胞的应激反应和恢复所必需的分子机制。具体来说： 目标 1. 达到 研究压力诱导翻译调节和恢复的机制，以检验我们的假设 热应激诱导的翻译重编程对于系统潜在恢复至关重要，并且是 神经元健康和生存的关键特征；目标 2. 研究浦肯野神经元中蛋白质稳态的破坏 小脑共济失调小鼠模型，以检验我的假设，即导致 RREB1 丢失的突变会改变 蛋白质降解，可能参与观察到的神经变性并使细胞更容易受到影响 细胞应激。已完成的博士前研究和拟议的 F99 研究创建了严格的学习计划 将应用于拟议的 K00 研究的神经元应激反应。拟议的 K00 研究将确定 导致更快发作或进行性神经退行性疾病的因素，以及不允许的因素 神经元从压力中恢复。 K00 的研究结果有望产生治疗靶点以延长 认知跨度并促进神经元从压力中恢复。