Vulnerability of Aging White Matter to Ischemia

老化白质对缺血的脆弱性

• 批准号: 8690720
• 负责人: Selva Baltan
• 金额: $ 29.72万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690720
• 关键词: AMPA Receptors; Age; Aging; Agonist; Animals; Antioxidants; Attenuated; Axon; Biochemical; Cause of Death; Cells; Clinical; Corpus Callosum; Depressed mood; Dynamin; Electrophysiology (science); Failure; Fiber; Free Radical Scavengers; Functional disorder; Generations; Glucose; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Gray unit of radiation dose; Health; Health Resources; Image; Immunohistochemistry; Injury; Ischemia; Ischemic Stroke; Kainic Acid Receptors; Link; Location; Measurement; Mediating; Mitochondria; Modeling; Mus; Neuraxis; Neurodegenerative Disorders; Optic Nerve; Oxidative Stress; Oxygen; Pathway interactions; Permeability; Predisposition; Preparation; Proteins; Reactive Oxygen Species; Recovery; Recruitment Activity; Reporting; Risk; Risk Factors; Role; Site; Slice; Societies; Stroke; Structure; Testing; Therapeutic; Up-Regulation; age related; cellular targeting; cost; deprivation; design; disability; excitotoxicity; improved; injured; mitochondrial dysfunction; phenylmethylpyrazolone; prevent; social; stroke therapy; therapeutic target; vascular factor; white matter; white matter damage; white matter injury

DESCRIPTION (provided by applicant): The risk for ischemic stroke increases drastically with age. Although this has been attributed to vascular factors, aging could result in changes such that the central nervous system (CNS) itself has an increased vulnerability to ischemic injury. White matter (WM) is injured in most strokes and axonal injury and dysfunction are responsible for much of the disability associated with clinical deficits. We suggest that failure to protect WM is one of the primary reasons contributing to the lack of successful stroke therapy. The long term goal is to determine if aging WM function can be improved in a model of ischemic injury by attenuating oxidative injury and by preserving mitochondrial integrity through blockade of age-specific excitotoxic pathways. Recently, we reported that CNS WM is intrinsically more vulnerable to ischemic injury in older animals. In young WM, the damage from ischemic injury involves the sequence of energy depletion (ionic pathway), excessive glutamate release (excitotoxicity), generation of reactive oxygen species and oxidative stress (oxidative pathway). Overactivation of either AMPA or kainate receptors in optic nerve but activation of Ca2+permeable AMPA receptors in corpus callosum mediate injury, suggesting a region specific mechanism of ischemic injury in young WM. In older WM, the injury is mediated by Ca2+independent excitotoxicity and an earlier and more robust glutamate release associated with upregulation of glutamate transporter GLT1. Our preliminary studies suggest that excitotoxicity leads to oxidative stress in aging WM associated with alterations in axonal mitochondrial dynamics. It is not known whether manipulating excitotoxicity in an age-specific manner can rescue axon function, reducing oxidative stress and maintaining mitochondrial dynamics. This proposal combines electrophysiology, immunohistochemistry, confocal imaging, biochemical measurements, and genetically modified mice to test the hypothesis that increased excitotoxicity is due to multiple release sites and release mechanisms of glutamate, activating age-specific glutamate receptors in a cell-specific manner, and that, this is responsible for increased vulnerability of aging WM to ischemia by disrupting mitochondrial dynamics and aggravating oxidative injury. The three specific aims of this proposal are designed to better understand the cellular sites and mechanisms that link excitotoxicity to oxidative injury and mitochondrial dysfunction during ischemia in aging WM. Acutely isolated optic nerve and corpus callosum slices will be used to ascertain quantitative measurements of WM function and structure. Our focus is to define appropriate age-specific therapeutic targets for stroke and other neurodegenerative diseases involving WM.

描述（由申请人提供）：缺血性中风的风险随着年龄的增长而急剧增加。尽管这归因于血管因素，但衰老可能会导致中枢神经系统（CNS）本身更容易遭受缺血性损伤。在大多数中风中，白质 (WM) 都会受到损伤，而轴突损伤和功能障碍是导致与临床缺陷相关的大部分残疾的原因。我们认为未能保护 WM 是导致中风治疗失败的主要原因之一。长期目标是确定是否可以通过减轻氧化损伤和通过阻断年龄特异性兴奋性毒性途径来保持线粒体完整性来改善缺血性损伤模型中的衰老 WM 功能。最近，我们报道老年动物的中枢神经系统 WM 本质上更容易受到缺血性损伤。在年轻的WM中，缺血性损伤造成的损害涉及能量消耗（离子途径）、谷氨酸过量释放（兴奋性毒性）、活性氧的产生和氧化应激（氧化途径）的顺序。视神经中 AMPA 或红藻氨酸受体的过度激活，但胼胝体中 Ca2+ 通透性 AMPA 受体的激活介导损伤，表明年轻 WM 缺血性损伤的区域特异性机制。在老年 WM 中，损伤是由 Ca2+ 独立的兴奋性毒性以及与谷氨酸转运蛋白 GLT1 上调相关的更早、更强的谷氨酸释放介导的。我们的初步研究表明，兴奋性毒性会导致衰老 WM 中的氧化应激，并与轴突线粒体动力学的改变相关。目前尚不清楚以特定年龄的方式操纵兴奋性毒性是否可以挽救轴突功能、减少氧化应激并维持线粒体动力学。该提案结合了电生理学、免疫组织化学、共焦成像、生化测量和转基因小鼠，以测试兴奋性毒性增加是由于谷氨酸的多个释放位点和释放机制导致的假设，以细胞特异性的方式激活年龄特异性谷氨酸受体，以及也就是说，这会破坏线粒体动力学并加剧氧化损伤，从而导致衰老的 WM 更容易发生缺血。该提案的三个具体目标旨在更好地了解老年 WM 缺血期间将兴奋性毒性与氧化损伤和线粒体功能障碍联系起来的细胞位点和机制。急性分离的视神经和胼胝体切片将用于确定 WM 功能和结构的定量测量。我们的重点是为中风和其他涉及 WM 的神经退行性疾病确定适当的年龄特异性治疗目标。