Vulnerability of Aging White Matter to Ischemia

老化白质对缺血的脆弱性

• 批准号: 9308535
• 负责人: Selva Baltan
• 金额: $ 32.72万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308535
• 关键词: Achievement; Affect; Age; Aging; Attenuated; Axon; Biochemical; Brain; Cause of Death; Cell physiology; Cells; Conduct Clinical Trials; Development; Disease; Electrophysiology (science); Epigenetic Process; Failure; Funding; Gene Proteins; Genetic; Genetic Transcription; Glucose; Goals; Health; Histone Deacetylase; Histone Deacetylase Inhibitor; Impairment; In Vitro; Injury; Ischemia; Light; MS-275; Mediating; Membrane Potentials; MicroRNAs; Mitochondria; Molecular; Mus; Neuroglia; Neurologic Dysfunctions; Neurons; Nitric Oxide Synthase; Oxidative Stress; Oxygen; Pathogenesis; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Physiological; Population; Protein Acetylation; Protein Isoforms; Recovery; Recovery of Function; Recruitment Activity; Regulation; Regulator Genes; Research; Risk; Role; Stroke; Structure; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; United States; age related; aging brain; base; cancer clinical trial; cell injury; cell motility; deprivation; design; disability; excitotoxicity; experience; experimental study; functional restoration; gray matter; in vivo; insight; mitochondrial dysfunction; mouse model; neuronal survival; novel; novel therapeutics; prevent; promoter; stroke therapy; white matter; white matter injury

Abstract Stroke is a leading cause of death and disability and the risk for stroke increases with age. The mechanisms that contribute to post-ischemic injury after stroke are not completely understood, and as a result most clinical trials conducted to date for stroke therapeutics have failed. Failure to consider white matter (WM) injury is a critical gap in the development of successful stroke therapy. As mechanisms of WM injury differ from those in gray matter and change with age, an ideal stroke therapeutic must not only be directed towards neuronal and axonal protection across age, but also must restore function when applied after injury. One of our significant research achievements during the previous funding cycle established that Class I HDAC activation contributes to excitotoxicity during ischemia and contributes to oxidative injury during the post-ischemic period by impairing mitochondrial structure and function. Class I HDAC inhibition promotes axon function recovery when applied before or after ischemia in young and aging WM through unknown mechanisms. Our current proposal focuses on the mechanisms of post-ischemic protection conferred by Class I HDAC inhibition in young and aging WM. While little is known about the gene regulatory mechanisms underlying this protective phenomenon, an intriguing reciprocal relationship has emerged between levels of HDACs and miRNAs affecting cellular survival following stroke. Among ischemia-regulated miRNAs, miR-331 is predicted to target Class I HDACs. Ischemia up-regulates Class I HDAC levels in young and aging WM. Our preliminary findings show that ischemia led to decreased levels of miR-331 concomitant with increased HDAC expression and HDAC inhibition upregulated miR-331 above control levels. Consequently, an miR-331 mimic suppresses HDAC levels, indicating a reciprocal regulation between Class I HDACs and miR-331. Furthermore, WM ischemia activates nitric oxide synthase (NOS), leading to oxidative injury via mitochondrial dysfunction, and Class I HDAC inhibition attenuates NOS activity. In light of this information, we propose to further extend these studies by testing our novel hypothesis that Class I HDAC activation mediates WM ischemic injury by contributing to increased oxidative stress, impairing mitochondrial function, and down-regulating glial expression of miR-331. Our overall goal is to determine whether Class I HDACs act directly or recruit NOS or interact with miR-331 to exert post-ischemic injury in young and aging WM. Electrophysiological, biochemical, and mouse genetic in vitro and in vivo approaches will be employed to test the following Specific Aims: Aim 1 is designed to investigate whether Class I HDAC activation recruits NOS in an age-, cell-, and isoform-specific manner; Aim 2 is designed to determine whether Class I HDAC activation directly mediates mitochondrial injury during ischemia; and Aim 3 is designed to establish whether Class I HDACs interact with miR-331 to mediate ischemic WM injury. Overall, the present project will unravel the role of Class I HDAC activity in WM ischemic injury in order to help in the design of novel therapies to minimize post-ischemic injury in patients.

摘要 中风是死亡和残疾的主要原因，中风的风险随着年龄的增长而增加。的机制 导致中风后缺血后损伤的因素还不完全清楚，因此，大多数临床 迄今为止进行的中风治疗试验都失败了。不考虑白色物质（WM）损伤是一种 在成功的中风治疗的发展的关键差距。由于WM损伤的机制不同于 灰质和随年龄的变化，理想的中风治疗必须不仅针对神经元， 轴突保护跨越年龄，但也必须恢复功能时，应用损伤后。我们的一个重要的 上一个资助周期的研究成果表明，I类HDAC激活有助于 在缺血期间的兴奋毒性，并有助于在缺血后期间的氧化损伤， 线粒体的结构和功能当应用时，I类HDAC抑制促进轴突功能恢复 缺血前或缺血后的青年和老年WM通过未知的机制。我们目前的建议侧重于 关于年轻和老年WM中I类HDAC抑制所赋予的缺血后保护机制。 虽然对这种保护现象背后的基因调控机制知之甚少，但 HDAC和影响细胞存活的miRNAs水平之间出现了有趣的相互关系 中风后在缺血调节的miRNA中，预测miR-331靶向I类HDAC。缺血 上调年轻和老年WM中的I类HDAC水平。我们的初步发现表明缺血导致了 miR-331水平降低伴随HDAC表达增加，HDAC抑制上调 miR-331高于对照水平。因此，miR-331模拟物抑制HDAC水平，表明miR-331模拟物抑制HDAC水平。 I类HDAC和miR-331之间的相互调节。此外，WM缺血激活一氧化氮 合酶（NOS），通过线粒体功能障碍导致氧化损伤，以及I类HDAC抑制 减弱NOS活性。根据这些资料，我们建议进一步扩大这些研究，测试我们的 一种新的假设，即I类HDAC激活通过增加脑缺血性损伤的发生率来介导WM缺血性损伤。 氧化应激、损害线粒体功能和下调miR-331的神经胶质表达。 我们的总体目标是确定I类HDAC是否直接作用或招募NOS或与miR-331相互作用， 在青年和老年WM中发挥缺血后损伤作用。电生理学、生物化学和小鼠遗传学 将采用体外和体内方法来测试以下具体目标：目标1旨在 研究I类HDAC激活是否以年龄、细胞和亚型特异性方式募集NOS;目的2 旨在确定I类HDAC激活是否直接介导线粒体损伤， 目的3旨在确定I类HDAC是否与miR-331相互作用以介导缺血; 缺血性WM损伤。总的来说，本项目将揭示I类HDAC活性在WM缺血中的作用。 损伤，以帮助设计新的治疗方法，以最大限度地减少患者的缺血后损伤。