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: 10367741
• 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/10367741
• 关键词: Acute; Area; Brain; Brain Ischemia; Cell Death; Cerebrum; Chelating Agents; Cytoplasm; Development; Disease; Divalent Cations; Drug usage; Event; Glucose; Glutamates; Goals; Heart Arrest; Hilar; Hippocampus (Brain); Homeostasis; Hour; Imaging Techniques; In Vitro; Injury; Intervention; Ions; Ischemia; Ischemic Brain Injury; Ischemic Neuronal Injury; Lead; 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; Ursidae Family; 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.项目摘要/摘要 对缺血性脑损伤的治疗很差，部分原因是我们对导致脑损伤的机制了解有限 神经细胞的丧失。而谷氨酸过度释放和神经元钙蓄积的作用很大 经过研究，最近的证据表明，另一种二价阳离子--锌离子--的关键贡献。在缺血后或 癫痫持续发作、神经元内游离锌离子蓄积及锌离子螯合保护作用的观察 与神经元死亡有关。培养研究表明，外源应用的锌离子可以进入 神经元聚集在线粒体中，严重破坏了它们的功能。然而，人们对此知之甚少。 内源性锌离子在天然脑组织中蓄积的损伤机制。 采用缺氧缺糖(OGD)所致急性海马区脑片缺血模型。 最近首次同时测量了细胞内锌离子和钙离子的变化，发现锌离子 堆积是海马锥体神经元中的一个早期事件，它先于并有助于随后的 急剧的和终末的钙离子释放事件，与膜完整性的丧失有关。我们还有更多 研究发现，锌离子的急性有害效应似乎是由于其通过线粒体吸收而产生的。 线粒体钙单转运体(MCU)。在正在进行的切片研究中，我们找到了证据表明， 海马CA1和CA3区锥体神经元中锌离子的来源与急性脑损伤的关系 OGD可致CA1区神经元线粒体大量锌蓄积，但对CA3区神经元无明显影响 在一次亚致死的OGD发作后延迟时间点。锌离子贡献的这些差异可能与 CA1和CA3神经元在疾病条件下的区别脆弱性，其中CA1优先退化 在短暂性全脑缺血后，CA3在复发性边缘癫痫发作后。 这一建议继续了正在进行的研究，通常围绕一个假设进行组织：线粒体锌离子 蓄积是短暂性脑缺血后的早期事件，它会导致线粒体功能中断和 导致延迟性细胞死亡。目的将成像技术应用于急性海马区切片，以进一步阐明 短暂性氧糖剥夺后海马神经元线粒体锌离子的作用 缺血模型)，并研究氧/葡萄糖恢复后发生的事件。 服从有益的治疗干预。AIM II试图对我们的原则研究进行初步测试 在体大鼠全脑缺血模型中的假说。 这些研究将提供机械性的见解，有助于开发新的有效的治疗方法 在短暂性脑缺血发作后进行干预，这将扰乱病理级联反应， 使结果得以改善。