Spreading Depolarizations and Neuronal Vulnerability

去极化的扩散和神经元的脆弱性

• 批准号: 10320027
• 负责人: Claude W Shuttleworth
• 金额: $ 32.61万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320027
• 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; 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.

项目摘要 该项目解决了有助于急性脑损伤进展的基本机制， 包括中风和创伤。我们的长期目标是制定可以在迟到的干预措施 时间点，最终将转换为临床研究，以提高生存率和质量 幸存者的生活。该项目侧重于扩散去极化现象（SD），该现象具有 最近出现了急性脑损伤进展的关键因素。最近的临床 现在，录音意味着重复的SD波会导致损害的进展多天，并且 创伤患者。现在的挑战是了解如何阻止破坏性的SD，或者如何阻止 支持受伤的脑组织，以在SD的有害影响中生存。因此，该项目解决了密钥 有关将SD与伤害联系起来的机制的知识差距。我们将使用大脑切片和动物模型 确定基本机制，这些机制是SD的破坏性影响的基础，以及支持的方法 损害组织以从重复的SD发作中恢复。我们的中心假设是代理人 有选择地降低单个SD事件的持续时间将减少情节性谷氨酸和Ca2+介导的持续时间 每次SD事件都会发作的神经元损伤。此外，保留 通过侵入周围组织的SD将保持大脑恢复所需的SD的有益影响。我们将 测试是否专门限制NMDA型谷氨酸受体的谷氨酸瞬变和/或激活 在SD的后期，将支持SD后神经元恢复。特定目标1检验假设 病理生理生理谷氨酸脉冲严格限制为SD，并在代谢中扩展 由于突触前的释放和代谢中星形胶质细胞调节的破坏而受损的组织受损 折衷的切片。特定目标2检验了以下假设，即针对SD的脆弱阶段将 促进神经元恢复代谢损害的组织。将评估神经元Ca2+负载， 以及用于确定改善CA2+负载恢复的方法的药理干预措施， 没有损害有益机制。特定的目标3对这些机制进行了关键测试 体内设置。在每个目标中将使用合并的成像和电生理方法， 在脑切片中表征的细胞机制（AIMS 1和2），然后在体内进行测试（AIM 3）。遗传 谷氨酸和钙编码的传感器将补充其他单神经元电生理学，并 成像方法。将测试药理学方法，以识别机制和 减少SD在代谢损害组织中的有害影响的干预措施。成功的 这些目标的完成应确定将SD与细胞损伤联系起来的基本机制 损害组织，并为可以开发的理性方法提供基础 在一系列急性脑损伤之后的关键日内采用干预措施。