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.

项目摘要 每个人都有有限数量的神经元，这些神经元必须忍受一生的环境 压力源。该提案的重点是研究神经元应力反应和恢复机制 与神经元功能和生存有关。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对非 - 典型的方式，通过下调翻译。返回基线条件时，这是可以迅速恢复的 在有限的窗口中，超出了细胞死亡。我们还发现压力反应因素是 在恢复过程中被激活，对于神经元细胞功能很重要。基于这些和其他原始 在关闭阶段的发现，我们的中心假设是神经元部分通过 翻译重编程以准备系统的生存，如果恢复是一种选择。测试 这个假设，我们发现神经元上调HSP70，以便在此恢复阶段生存。有趣的是， HSP70的上调已被证明与多种神经退行性疾病有关，包括 阿尔茨海默氏病。在F99阶段提出的研究的基本原理是分子 在热应激期间介导神经元功能和生存的程序知之甚少，进一步 理解将为影响人类紧张的压力源的根本原因提供批判性洞察力 健康与疾病的系统。鉴于神经元压力反应对人类健康的重要性， 拟议的研究的远程目标是了解功能失调的压力反应在 神经变性及其如何有助于降低神经元应力的韧性和无法从 压力。我们将通过生化，分子，细胞和物理测量来做到这一点，以表征 神经元细胞和分子机制的应力反应对于恢复必不可少的。具体：目标1。 研究压力诱导的翻译调节和恢复的机制，以检验我们的假设 热应力引起的翻译重编程对于准备系统的潜在恢复至关重要，并且是 神经元健康和生存的关键特征；目的2。研究浦肯野神经元中的蛋白质抑制 小脑共济失调的小鼠模型，以测试我的假设，即突变导致RREB1的损失改变了 蛋白质降解，可能参与观察到的神经变性并使细胞更易感 到细胞应激。完整的五型和拟议的F99研究创建了一个严格的研究计划 神经元应力反应将应用于拟议的K00研究。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 从压力中恢复神经元。 K00的发现持有产生治疗靶标的延伸的承诺 认知井跨度并促进压力中的神经元恢复。