Non-canonical mechanisms of excitotoxicity

兴奋性毒性的非典型机制

• 批准号: 10679904
• 负责人: Michael Bennett
• 金额: $ 3.96万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679904
• 关键词: Acute Brain Injuries; Address; Animal Model; Area; Blood Vessels; Brain; Brain Injuries; Cations; Cells; Cerebrovascular Circulation; Cessation of life; Clinical; Clinical Trials; Complex; Distal; Electrophysiology (science); Event; Failure; Future; Glutamates; Goals; Homeostasis; Hour; Imaging Techniques; Infarction; Injury; Intervention; Intervention Studies; Ischemia; Ischemic Stroke; Knock-out; Link; Literature; Measures; Mediating; Metabolic; Methods; Modeling; Mus; N-Methylaspartate; Neuronal Injury; Neurons; Outcome; Pathway interactions; Patients; Prevention; Proteins; Recovery; Research; Role; Slice; Source; Stroke; System; Testing; Therapeutic Intervention; Tissues; Toxic effect; Translating; Work; brain tissue; cell injury; chelation; clinically relevant; excitotoxicity; experimental study; extracellular; fluorescence imaging; hypoperfusion; imaging approach; improved; in vivo; in vivo Model; knock-down; neuroprotection; neurotoxic; novel; novel strategies; pharmacologic; postsynaptic; pre-clinical; presynaptic; prevent; receptor; stroke model; therapeutic target; uptake; voltage

PROJECT SUMMARY This project addresses the underlying mechanisms that progress ischemic damage of vulnerable tissue that surround acute brain injuries such as stroke. Our long-term goal is to identify the specific mechanisms that transition metabolically compromised tissue to damaged, pro-death penumbra and to develop clinically relevant therapeutic targets to improve patient survival after brain injury. While understanding of ischemic methods of neuronal injury has been the primary focus, exploring specific mechanisms of consequence and potential therapeutic targets has lagged far behind. This project looks specifically at Spreading Depolarizations (SDs) which have recently been identified as contributing significantly to the progression of injury in vulnerable penumbra. The main focus of these events has been on their contribution to prolonged NMDA-mediated Ca2+ influx and subsequent damage. However, SDs present a much more complex and underexplored surge of pre- synaptic cation release and post-synaptic uptake through alternate pathways. Specifically both post-synaptic activation of voltage-gated Ca2+ channels and increase in extracellular Zn2+ release and uptake have been linked to the initiation and subsequent propagation of SD. Our central hypothesis is that SD-induced injury progression in metabolically depleted tissue is mediated by dysregulation of non-NMDA-centric cation homeostasis. Furthermore, agents that are selective to reduce alternative Ca2+ channel activation and/or decrease post- synaptic Zn2+ uptake will reduce the downstream mediated damage that occurs following SD. We will use brain slice and animal models to explore Zn2+ and Ca2+ specific mechanisms of injury as well as pharmacological intervention to support compromised tissue during and after onset of SD. Specific Aim 1 focuses on the hypothesis that neuronal voltage-gated Ca2+ channels contribute to post-synaptic uptake of intracellular Ca2+ and lead to downstream cell execution. Neuronal Ca2+ loading will be assessed using a specific genetically modified model and pharmacological intervention will be used to assess recovery in a metabolically compromised tissue setting. Specific Aim 2 tests the hypothesis that disruption of Zn2+ homeostasis contributes to mechanisms of SD-induced injury in vulnerable setting. Zn2+ wave in vulnerable tissue and specific stores of Zn2+ will be assessed to explore where damaging levels are released. Specific Aim 3 then assess these mechanisms in an in vivo setting. In all aims, both electrophysiological and imaging techniques will be used to assess specific mechanisms in brain slice (Aim 1 and 2) and then translate into in vivo model (Aim 3). Pharmacological intervention and specific knockdown models will explore where these cations contributions to damage and identify where damaging levels of these cations originate. Completion of these aims should ascertain specific mechanisms of Ca2+ and Zn2+-mediated injury following SD in vulnerable tissue and propose potential targets for clinical prevention paradigms.

项目摘要 该项目解决了易受伤害组织的缺血损害的潜在机制 围绕急性脑损伤，例如中风。我们的长期目标是确定特定机制 过渡代谢折衷的组织，以损伤，死亡的阴茎并发展临床相关的组织 治疗靶标可改善脑损伤后患者生存。同时了解的缺血方法 神经元损伤一直是主要重点，探索了后果和潜力的特定机制 治疗靶标远远落后。该项目专门考虑扩散去极化（SDS） 最近被确定为对弱势损害的进展显着贡献 penumbra。这些事件的主要重点是它们对长时间NMDA介导的Ca2+的贡献 涌入和随后的损害。然而，SD的前提是，前的更为复杂和不充分的浪涌 突触阳离子释放和突触后通过替代途径的吸收。特别是两次突触后 电压门控Ca2+通道的激活以及细胞外Zn2+释放和吸收的增加已连接 SD的启动和随后的传播。我们的中心假设是SD诱导的损伤进展 在代谢中耗尽的组织中，通过非以NMDA为中心的阳离子稳态的失调介导。 此外，选择性降低替代Ca2+通道激活和/或减少后的药物 突触Zn2+摄取将减少SD后发生的下游介导的损伤。我们将使用大脑 切片和动物模型，以探索Zn2+和Ca2+损伤的特定机制以及药理学 在SD发作期间和之后，干预以支持损害的组织。特定目标1专注于 假设神经元电压门控Ca2+通道有助于细胞内Ca2+的突触后摄取 导致下游电池执行。神经元Ca2+负载将使用特定的遗传修饰进行评估 模型和药理干预措施将用于评估代谢损害组织中的恢复 环境。特定目标2检验了Zn2+稳态的破坏有助于机制的假设 SD诱导的脆弱环境受伤。脆弱的组织中的Zn2+波浪将是Zn2+的特定存储 评估以探索释放破坏水平的位置。特定目标3然后评估这些机制 体内设置。总体而言，电生理和成像技术都将用于评估特定 大脑切片中的机制（AIM 1和2），然后转化为体内模型（AIM 3）。药理 干预和特定的敲低模型将探索这些阳离子对损伤和 确定这些阳离子的破坏水平起源。这些目标的完成应确定具体 SD在脆弱组织中SD后Ca2+和Zn2+介导的损伤的机制，并提出了潜在的目标 临床预防范例。