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 该项目涉及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，并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。该项目的重点是扩散去极化（SD）现象， 最近出现的急性脑损伤的延迟进展的一个关键因素。最近的临床 现在的记录表明，重复的SD波会导致中风中损害的进展， 创伤病人现在的挑战是了解如何阻止破坏性的SD，或者如何 支持受伤的脑组织在SD的有害影响中存活。因此，该项目解决了关键 关于将SD与损伤联系起来的机制的知识缺口。我们将使用脑切片和动物模型， 确定造成可持续发展破坏性影响的基本机制，以及支持可持续发展的方法。 受损组织从反复的SD发作中恢复。我们的中心假设是， 选择性地减少单个SD事件的持续时间将减少发作性谷氨酸和Ca 2+介导的 神经元损伤与每个SD事件一起发生。此外，保持传播 通过梗塞周围组织的SD将保持脑恢复所需的SD的有益效果。我们将 测试是否限制谷氨酸瞬变和/或NMDA型谷氨酸受体的激活， 将支持SD后的神经元恢复。具体目标1检验假设 病理生理谷氨酸脉冲严格限于SD，并在代谢中延长， 受损的组织，由于突触前释放和破坏星形胶质细胞的调节，在代谢 受损切片具体目标2检验了这样一个假设，即针对SD的脆弱阶段， 促进代谢受损组织的神经元恢复。将评价神经元Ca 2+负荷， 和药理学干预，用于确定改善Ca 2+负荷恢复的方法， 而不损害有益的机制。具体目标3使这些机制的关键测试在一个 体内设置。将在每个目标中使用联合成像和电生理方法， 在脑切片中表征细胞机制（目的1和2），然后在体内测试（目的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学， 成像方法。将对药理学方法进行测试，以确定机制， 减少SD在代谢受损组织中的有害作用的干预。成功 这些目标的完成应确定联系SD细胞损伤的基本机制， 受损的组织，并提供合理的方法，可以开发的基础， 在一系列急性脑损伤后的关键日子里进行干预。