Spreading Depolarizations and Neuronal Vulnerability

去极化的扩散和神经元的脆弱性

• 批准号: 10083239
• 负责人: Claude W Shuttleworth
• 金额: $ 32.64万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083239
• 关键词: Acute Brain Injuries; Address; Animal Model; Animals; Astrocytes; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; Calcium; Characteristics; Clinic; Clinical; Clinical Management; Clinical Research; Complement; Data; Electrophysiology (science); Event; Funding; Future; Glutamate Receptor; Glutamates; Goals; Image; Impairment; Individual; Infarction; Injury; Intervention; Ischemia; Knowledge; Lesion; Link; Mediating; Mental Depression; Metabolic; Methods; Modeling; N-Methylaspartate; Neuronal Injury; Neurons; Pathway interactions; Patients; Pharmacology; Phase; Physiologic pulse; Process; Quality of life; Recovery; Recovery of Function; Regulation; Slice; Stroke; Structure; Survivors; Testing; Thinking; Time; Tissues; Trauma; Trauma patient; Traumatic Brain Injury; Work; base; brain tissue; cell injury; experimental study; imaging approach; improved; in vivo; in vivo Model; in vivo evaluation; injury recovery; neurotrophic factor; preconditioning; preservation; presynaptic; prevent; protective effect; remote location; repaired; sensor; stroke patient; targeted agent; two-photon

PROJECT SUMMARY This project addresses fundamental mechanisms that contribute to the progression of acute brain injuries, including stroke and trauma. Our long-term goal is to develop interventions that can be applied at late time points, and which ultimately will be translatable to clinical studies to improve survival, and quality of life of survivors. The project focuses on the phenomenon of Spreading Depolarization (SD), which has recently emerged as a key contributor to the delayed progression of acute brain injuries. Recent clinical recordings now imply that repetitive SD waves cause progression of damage for many days in stroke and trauma patients. The challenge now is to understand how to block damaging SDs, or alternatively how to support injured brain tissue to survive deleterious effects of SD. This project therefore addresses key gaps in knowledge about mechanisms linking SD to injury. We will use brain slices and animal models to identify fundamental mechanisms that underlie damaging effects of SD, and approaches to support compromised tissues to recover from repeated SD episodes. Our central hypothesis is that agents that selectively reduce the duration of individual SD events will reduce episodic glutamate and Ca2+-mediated neuronal injury that occurs episodically with each SD event. Furthermore, preserving the propagation of SDs through peri-infarct tissues will maintain beneficial effects of SD required for brain recovery. We will test whether limiting glutamate transients and/or activation of NMDA-type glutamate receptors specifically during the late phase of SD will support neuronal recovery after SD. Specific Aim 1 tests the hypothesis that pathophysiological glutamate pulses are strictly limited to SD, and extended in metabolic compromised tissues, due to presynaptic release and disruption of astrocytic regulation in metabolically compromised slices. Specific Aim 2 tests the hypothesis that targeting the vulnerable phase of SD will promote neuronal recovery metabolically compromised tissues. Neuronal Ca2+ loading will be evaluated, and pharmacological interventions used to identify approaches to improve recovery of Ca2+ loading, without impairing beneficial mechanisms. Specific Aim 3 makes key tests of these mechanisms in an in vivo setting. Combined imaging and electrophysiological methods will be used throughout each aim, with cellular mechanisms characterized in brain slices (Aims 1&2) and then tested in vivo (Aim 3). Genetically- encoded sensors for glutamate and calcium will complement other single-neuron electrophysiological and imaging approaches. Pharmacological approaches will be will be tested to identify mechanisms and interventions that reduce deleterious effects of SD in metabolically compromised tissues. Successful completion of these aims should identify fundamental mechanisms linking SD to cellular injury in compromised tissues, and provide the basis for rational approaches that can be developed for interventions applied in the critical days following a range of acute brain injuries.

项目概要 该项目探讨了导致急性脑损伤进展的基本机制， 包括中风和外伤。我们的长期目标是开发可以在后期应用的干预措施 时间点，最终将转化为临床研究，以提高生存率和质量 幸存者的生活。该项目重点关注传播去极化（SD）现象，该现象已 最近被发现是急性脑损伤延迟进展的关键因素。近期临床 现在的记录表明，重复的 SD 波会导致中风和中风患者的损伤持续多日。 外伤患者。现在的挑战是了解如何阻止破坏性的 SD，或者如何 支持受伤的脑组织抵御 SD 的有害影响。因此，该项目解决了关键 关于 SD 与损伤的联系机制的知识存在差距。我们将使用脑切片和动物模型来 确定可持续发展破坏性影响的基本机制以及支持方法 受损组织从重复的 SD 发作中恢复。我们的中心假设是，代理人 选择性地减少单个 SD 事件的持续时间将减少偶发性谷氨酸和 Ca2+ 介导的 每次 SD 事件都会偶发性发生神经元损伤。此外，保留传播 通过梗塞周围组织的 SD 将维持大脑恢复所需的 SD 的有益作用。我们将 测试是否特异性地限制谷氨酸瞬态和/或 NMDA 型谷氨酸受体的激活 SD 后期期间的治疗将支持 SD 后神经元的恢复。具体目标 1 检验假设 病理生理学谷氨酸脉冲严格限于 SD，并在代谢中扩展 由于突触前释放和代谢中星形胶质细胞调节的破坏而导致组织受损 受损的切片。具体目标 2 检验了以下假设：针对 SD 的脆弱阶段将 促进代谢受损组织的神经元恢复。将评估神经元 Ca2+ 负荷， 以及用于确定改善 Ca2+ 负荷恢复的方法的药物干预措施， 而不损害有益机制。具体目标 3 对这些机制进行了关键测试 体内设置。结合成像和电生理学方法将在每个目标中使用， 在脑切片中表征细胞机制（目标 1 和 2），然后在体内进行测试（目标 3）。从基因上来说—— 谷氨酸和钙的编码传感器将补充其他单神经元电生理和 成像方法。将测试药理学方法以确定机制和 减少 SD 对代谢受损组织的有害影响的干预措施。成功的 完成这些目标应确定 SD 与细胞损伤之间的联系的基本机制 受损组织，并为可开发的合理方法提供基础 在一系列急性脑损伤后的关键日子里采取的干预措施。