Mitochondrial Zn2+ accumulation and the induction of ischemic neurodegeneration

线粒体 Zn2 积累和缺血性神经变性的诱导

• 批准号: 10553137
• 负责人: JOHN H WEISS
• 金额: $ 56.17万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553137
• 关键词: Acute; Area; Binding; Brain; Brain Ischemia; Cell Death; Cerebrum; Chelating Agents; Cytoplasm; Development; Disease; Divalent Cations; Drug usage; Event; Glucose; Glutamates; Goals; Heart Arrest; Hilar; Hippocampus; Homeostasis; Hour; Imaging Techniques; In Vitro; Injury; Intervention; Ions; Ischemia; Ischemic Brain Injury; Ischemic Neuronal Injury; Link; Measurement; Membrane; Mitochondria; Modeling; Morbidity - disease rate; Motion; N-Methylaspartate; Nerve Degeneration; Neuronal Injury; Neurons; Oxygen; Pathogenicity; Pathologic; Pharmacotherapy; Play; Population; Preparation; Process; Rattus; Recurrence; Reperfusion Therapy; Research Personnel; Role; Seizures; Severities; Site; Slice; Source; Synapses; Testing; Therapeutic Intervention; Time; aging population; antagonist; brain tissue; chelation; deprivation; disability; excitotoxicity; follow-up; hippocampal pyramidal neuron; improved; improved outcome; in vivo; in vivo Model; insight; ischemic injury; loss of function; mitochondrial dysfunction; mortality; neuron loss; neuroprotection; novel strategies; postsynaptic; preservation; protective efficacy; restoration; stroke model; stroke therapy; synaptic function; therapeutically effective; uptake

7. Project Summary/Abstract Therapy for ischemic brain injury is poor in part because of our limited understanding of mechanisms leading to neuronal loss. While roles of excessive glutamate release and neuronal Ca2+ accumulation have been much studied, recent evidence implicates critical contributions of another divalent cation, Zn2+. After ischemia or prolonged seizures, free Zn2+ accumulates in neurons and observations that Zn2+ chelation is protective implicates a role in neuronal death. Culture studies have revealed that exogenously applied Zn2+ can enter neurons and accumulate in mitochondria, powerfully disrupting their function. However, little is known about mechanisms of injury caused by the accumulation of endogenous Zn2+ in native brain tissues. Using acute hippocampal slices subjected to oxygen glucose deprivation (OGD) to model ischemia, we recently made the first simultaneous measurements of cytosolic Zn2+ and Ca2+ changes, and found that Zn2+ accumulation is an early event in hippocampal pyramidal neurons that precedes and contributes to a subsequent sharp and terminal Ca2+ deregulation event, causatively linked to loss of membrane integrity. We have further found that the acute deleterious effects of Zn2+ seem to result specifically from its uptake into mitochondria via the mitochondrial Ca2+ uniporter (MCU). In ongoing slice studies, we find evidence for major differences between sources of the Zn2+ that accumulates in hippocampal CA1 and CA3 pyramidal neurons contributing to acute OGD induced damage, with considerable Zn2+ accumulation in mitochondria of CA1 but not of CA3 neurons at delayed time points after a sublethal episode of OGD. These differences in Zn2+ contributions may bear upon the differential vulnerabilities of CA1 vs CA3 neurons in disease conditions, with CA1 preferentially degenerating after transient global ischemia, and CA3 after recurrent limbic seizures. This proposal continues ongoing studies, generally organized around a Hypothesis: Mitochondrial Zn2+ accumulation is an early event after transient ischemia, which causes disruption of mitochondrial function and contributes to delayed cell death. Aim I applies imaging techniques to acute hippocampal slices to further clarify mitochondrial effects of Zn2+ in hippocampal neurons in the hours after transient oxygen glucose deprivation (as a model of ischemia), and to study events occurring after restoration of O2/glucose (“reperfusion”) that may be amenable to beneficial therapeutic interventions. Aim II seeks to make initial test of principle studies of our hypothesis in an in vivo rat global ischemia model. These studies will provide mechanistic insights that will aid the development of new and effective therapeutic interventions to be delivered after an episode of transient ischemia, that will disrupt the pathological cascade, enabling improved outcomes.

7.项目总结/摘要 缺血性脑损伤的治疗很差，部分原因是我们对导致缺血性脑损伤的机制了解有限。 神经元的丧失虽然谷氨酸的过度释放和神经元内钙的积累的作用已被许多研究者所证实， 最近的研究表明，另一种二价阳离子Zn 2+的重要贡献。缺血后或 长时间的癫痫发作，游离Zn 2+在神经元中积累，并且观察到Zn 2+螯合具有保护作用， 在神经元死亡中起作用培养研究表明，外源施加的Zn 2+可以进入 神经元和积累在线粒体，有力地破坏他们的功能。然而，人们对 内源性Zn 2+在脑组织中的积累引起的损伤机制。 采用急性海马脑片缺氧缺糖（OGD）模型， 最近首次同时测量了细胞内Zn 2+和Ca 2+的变化，发现Zn 2 + 蓄积是海马锥体神经元中的早期事件，其先于并促成随后的神经元内蓄积。 急剧和终端Ca 2+失调事件，因果关系与膜完整性的损失。我们进一步 发现Zn 2+的急性有害作用似乎是通过其进入线粒体而引起的， 线粒体Ca ~（2+）单向转运体（MCU）。在正在进行的切片研究中，我们发现了 在海马CA 1和CA 3锥体神经元中积累的Zn 2+的来源有助于急性 OGD诱导的损伤，在CA 1而不是CA 3神经元的线粒体中有相当多的Zn 2+积累， OGD亚致死性发作后延迟的时间点。Zn 2+贡献的这些差异可能与 疾病条件下CA 1与CA 3神经元的差异脆弱性，其中CA 1优先退化 短暂性全脑缺血后，以及复发性边缘癫痫发作后的CA 3。 这项建议继续进行中的研究，通常围绕一个假设组织：线粒体Zn 2 + 蓄积是短暂性缺血后的早期事件，其导致线粒体功能的破坏， 导致细胞延迟死亡。目的应用影像学技术研究急性海马脑片， 在短暂的氧糖剥夺后，Zn 2+对海马神经元线粒体的影响 缺血模型），并研究在恢复O2/葡萄糖（“再灌注”）后发生的事件， 适合于有益的治疗干预。目的二是对我们的原则研究进行初步测试。 在体内大鼠全脑缺血模型中， 这些研究将提供机制的见解，这将有助于开发新的和有效的治疗方法。 在短暂性缺血发作后进行干预，这将破坏病理级联反应， 使成果得到改善。