Neuroprotection by a Secreted Component of the Cellular Stress Response

细胞应激反应的分泌成分的神经保护作用

• 批准号: 10711886
• 负责人: Ulrich Hengst
• 金额: $ 30.64万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10711886
• 关键词: Affect; Alzheimer' s Disease; Binding; Brain; Cell Survival; Cells; Cellular Stress; Degenerative Disorder; Exposure to; Genetic Transcription; Homeostasis; Membrane; Mitochondria; Nerve Degeneration; Nervous System; Neurons; Oxidation-Reduction; Oxidative Stress; Paracrine Communication; Pathway interactions; Peptides; Process; Production; Protein Fragment; Reaction; Research Project Grants; SHH gene; Signal Transduction; Signaling Molecule; Stimulus; Stress; Testing; biological adaptation to stress; early detection biomarkers; experimental study; improved; intercellular communication; mitochondrial fitness; nanomolar; neuroprotection; novel; programs; promote resilience; resilience; response; transcription factor; transmission process

PROJECT SUMMARY We propose that the secreted luminal domain of the ER membrane-bound transcription factor CREB3L2, TAILS, is a signal for the transmission of adaptive cell stress response in neurons. Previously, we discovered that CNS neurons exposed to variety of degenerative stimuli, including oxidative stress, secrete TAILS. Application of TAILS in a low nanomolar concentration to primary neurons improved survival under oxidative stress. TAILS acts by increasing SHH signaling and increasing the mitochondrial fitness and redox capacity in stressed neurons. In our preliminary experiments, we found that TAILS boosts neuronal resilience not only against oxidative insults but also against stress triggered by the application of the Alzheimer's disease peptide oligomeric Aβ1-42. In this proposal, we are testing our general hypothesis that activation of the integrated stress response in neurons in AD brain triggers the production and secretion of TAILS, which acts as a paracrine signal enhancing SHH signaling thereby boosting resilience to Aβ1-42-induced neuronal stress. The successful completion of this research project will uncover a novel non-cell autonomous branch of adaptive stress signaling that is activated in neurons in response neurodegenerative stress and confers enhanced resilience and mitochondrial function to receiving cells. The expected results from this project will establish TAILS as a stress-regulated modulator of protective neuronal SHH signaling in AD, and it will provide evidence for intercellular communication of the ISR in the mammalian nervous system with implications for neurodegenerative conditions. Moreover, this project will lay the groundwork for two major new directions: (1) the requirement of cell stress for the secretion of TAILS suggests that it might be useful as a biomarker for early degenerative conditions in the brain; and (2) TAILS (or peptides derived from it) are potential compounds for boosting neuronal resilience in the context of AD and other degenerative conditions.

项目概要 我们提出 ER 膜结合转录因子 CREB3L2 的分泌管腔结构域， TAILS，是神经元中传递适应性细胞应激反应的信号。 暴露于各种退行性刺激（包括氧化应激）的中枢神经系统神经元会分泌TAILS。 将低纳摩尔浓度的 TAILS 应用到原代神经元可提高氧化条件下的存活率 TAILS 通过增加 SHH 信号传导并增加线粒体的适应性和氧化还原能力来发挥作用。 在我们的初步实验中，我们发现 TAILS 不仅可以增强神经元的恢复能力。 对抗氧化损伤，还对抗阿尔茨海默氏病引发的压力 肽寡聚 Aβ1-42 在此提案中，我们正在测试我们的一般假设，即激活 AD 大脑神经元的综合应激反应触发 TAILS 的产生和分泌，TAILS 发挥作用 作为旁分泌信号增强 SHH 信号传导，从而增强对 Aβ1-42 诱导的神经元应激的恢复能力。 该研究项目的成功完成将揭示一个新的非细胞自主分支 适应性应激信号在神经元中被激活以响应神经退行性应激并赋予 该项目的预期结果将是增强接收细胞的弹性和线粒体功能。 将 TAILS 建立为 AD 中保护性神经元 SHH 信号传导的应激调节调节剂，它将提供 哺乳动物神经系统中 ISR 细胞间通讯的证据对 此外，该项目将为两个主要新方向奠定基础：（1） 细胞应激对 TAILS 分泌的要求表明，它可能可用作 TAILS 的生物标志物 大脑的早期退化状况；(2) TAILS（或由其衍生的肽）是潜在的化合物 用于增强 AD 和其他退行性疾病中的神经恢复能力。