The Unfolded Protein Response and Neuroprotection in Stroke

中风中未折叠的蛋白质反应和神经保护

• 批准号: 9219590
• 负责人: Wei Yang
• 金额: $ 34.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9219590
• 关键词: Apoptosis; Autophagocytosis; Binding Proteins; Boxing; Brain; Cell physiology; Cells; Cellular Stress; Clinical Research; Couples; Data; Disease; Endoplasmic Reticulum; Enhancers; Enzymes; Future; Gene Expression Profile; Gene Expression Profiling; Goals; Health; Homeostasis; Individual; Infarction; Inhibition of Apoptosis; Inositol; Intervention; Ischemic Stroke; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Link; Mediating; Medical; Membrane; Messenger RNA; Middle Cerebral Artery Occlusion; Mission; Modeling; Modification; Molecular; Mus; Nervous System Physiology; Neurologic Deficit; Neurons; Neuroprotective Agents; Outcome; PERK kinase; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Patients; Play; Post-Translational Protein Processing; Process; Protein Biosynthesis; Protein Kinase; Protein Synthesis Inhibition; Proteins; Prunella vulgaris; Public Health; Quality of life; RNA; RNA Splicing; Reaction; Recovery; Research; Resistance; Reticulum; Role; Stress; Stroke; Testing; Therapeutic; Transgenic Mice; Work; abstracting; activating transcription factor; base; biological adaptation to stress; design; endoplasmic reticulum stress; gain of function; improved; inhibitor/antagonist; innovation; loss of function; mouse model; neuroprotection; novel strategies; novel therapeutic intervention; protein degradation; protein folding; protein function; protein misfolding; response; restoration; sensor; thrombolysis

Abstract Ischemic stroke is a devastating medical condition for which no pharmacologic intervention is available, except thrombolysis that can be used only for a small percentage of stroke patients. To improve stroke outcome, new pharmacologic approaches must be considered, such as boosting endogenous pro-survival pathways. Here, the unfolded protein response (UPR) is a promising target, because the UPR restores endoplasmic reticulum (ER) function, which is critical for survival of stressed cells. The ER plays a pivotal role in folding and processing newly synthesized proteins. ER function is impaired in a variety of stress conditions, including stroke, which results in accumulation of unfolded/misfolded proteins in the ER, a condition called ER stress. To resolve ER stress, the UPR activates adaptive responses that are mediated by 3 stress sensors in the ER membrane – activating transcription factor-6 (ATF6), inositol-requiring enzyme-1 (IRE1), and protein kinase RNA-like ER kinase (PERK). These UPR branches have 3 primary functions: 1) increase protein-folding capacity, 2) decrease the ER load, and 3) eliminate accumulated unfolded/misfolded proteins from the ER. The UPR also modulates other pro-survival pathways including O-linked β-N-acetylglucosamine (O-GlcNAc) modification. Although we know that stroke impairs ER function and activates the UPR, we do not yet know how the individual UPR branches define the fate and function of post-ischemic neurons in stroke, nor which UPR branch or branches play a predominant role in stroke outcome. Such knowledge is essential to developing a novel strategy to harness UPR pro-survival pathways for therapeutic benefits in stroke. Our long- term goal is to develop strategies to boost UPR pro-survival pathways for therapeutic purposes in stroke. The objective of this application is to establish the mechanistic link between the UPR and stroke outcome, and to identify the UPR branch or branches that critically define recovery of neurologic function after stroke. Our central hypothesis is that boosting pro-survival UPR and related pathways facilitates restoration of impaired ER function and cellular homeostasis in post-ischemic neurons, thereby improving stroke outcome. Based on our new unique UPR-selective and neuron-specific genetically modified mouse models, the hypothesis will be tested in the following specific aims: 1) Determine the role of ATF6 activation in stroke outcome; 2) Determine the contribution of the IRE1/XBP1/O-GlcNAc axis to stroke outcome; 3) Determine the role of the PERK branch in post-ischemic protein synthesis and stroke outcome. The proposed research is significant because we expect to uncover the mechanisms that link the UPR and downstream pathways to stroke outcome. Such knowledge will be a pivotal platform for future studies aimed at establishing new and innovative approaches to improve recovery of neurologic function after stroke, which critically defines quality of life for stroke patients.

摘要 缺血性中风是一种毁灭性的医学疾病，除了 血栓溶解只能用于一小部分中风患者。为了改善卒中结局， 必须考虑药理学方法，例如增强内源性促存活途径。在这里， 未折叠蛋白反应（UPR）是一个很有前途的靶点，因为UPR可以恢复内质网 (ER)功能，这对应激细胞的存活至关重要。ER在折叠中起着关键作用， 处理新合成的蛋白质。ER功能在多种应激条件下受损，包括 中风，这导致未折叠/错误折叠的蛋白质在ER中积累，这种情况称为ER应激。到 解决ER压力，UPR激活由ER中的3个压力传感器介导的适应性反应 膜激活转录因子6（ATF 6）、肌醇需要酶1（IRE 1）和蛋白激酶 RNA样ER激酶（PERK）。这些UPR分支有3个主要功能：1）增加蛋白质折叠 容量，2）降低ER负荷，和3）从ER消除累积的未折叠/错误折叠蛋白质。的 UPR还调节其他促生存途径，包括O-连接β-N-乙酰葡糖胺（O-GlcNAc） 改性虽然我们知道中风损害ER功能并激活UPR，但我们还不知道 单个UPR分支如何定义中风中缺血后神经元的命运和功能， UPR分支或分支在卒中结局中起主导作用。这些知识对于 开发一种新的策略，利用UPR促生存途径治疗中风的好处。我们长久以来- 长期目标是开发策略，以促进UPR促生存途径，用于治疗中风。的 本申请的目的是建立普遍定期审议和中风结果之间的机制联系， 确定UPR分支或关键定义卒中后神经功能恢复的分支。我们 中心假设是，促进促生存UPR和相关途径促进受损ER的恢复 缺血后神经元的功能和细胞内稳态，从而改善卒中结局。基于我们 新的独特的UPR选择性和神经元特异性转基因小鼠模型，该假设将是 在以下特定目的中进行测试：1）确定ATF 6激活在中风结果中的作用; 2）确定 IRE 1/XBP 1/O-GlcNAc轴对卒中结局的贡献; 3）确定PERK分支的作用 在缺血后蛋白质合成和中风结果中的作用。这项研究意义重大，因为我们 期望揭示UPR和下游通路与卒中结局之间的联系机制。等 知识将是未来研究的关键平台，旨在建立新的和创新的方法， 改善中风后神经功能的恢复，这决定了中风患者的生活质量。