Vulnerability of Aging White Matter to Ischemia

老化白质对缺血的脆弱性

基本信息

批准号：
10172740
负责人：
Selva Baltan
金额：
$ 31.04万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10172740
关键词：
Achievement Affect Age Aging Attenuated Axon Biochemical Genetics Brain Cause of Death Cell physiology Cells Conduct Clinical Trials Development Disease Electrophysiology (science)Epigenetic Process Failure Funding Gene Proteins 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 Regulation Regulator Genes Research 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 ischemic injury mitochondrial dysfunction mouse genetics mouse model neuronal survival novel novel therapeutics oxidative damage post stroke preservation prevent promoter recruit stroke risk stroke therapy white matter white matter injury

项目摘要

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.

抽象的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。机制导致中风后缺血性损伤的因素尚不完全清楚，因此大多数临床迄今为止进行的中风治疗试验均已失败。不考虑白质（WM）损伤是一种成功中风治疗发展的关键差距。由于 WM 损伤的机制不同于灰质随年龄的变化而变化，理想的中风治疗不仅必须针对神经元和跨年龄的轴突保护，但在受伤后使用时也必须恢复功能。我们的重要意义之一上一个资助周期的研究成果证实 I 类 HDAC 激活有助于缺血期间的兴奋性毒性，并通过损害缺血后时期的氧化损伤线粒体的结构和功能。应用 I 类 HDAC 抑制可促进轴突功能恢复通过未知的机制在年轻和老年 WM 中发生缺血之前或之后。我们目前的提案重点 I 类 HDAC 抑制在年轻和老年 WM 中所赋予的缺血后保护机制。虽然人们对这种保护现象背后的基因调控机制知之甚少，影响细胞存活的 HDAC 和 miRNA 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，miR-331 预计会靶向 I 类 HDAC。缺血上调年轻和老年 WM 中的 I 类 HDAC 水平。我们的初步研究结果表明，缺血导致 miR-331 水平降低，同时 HDAC 表达增加，且 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 I 类 HDAC 和 miR-331 之间的相互调节。此外，WM 缺血会激活一氧化氮合成酶 (NOS)，通过线粒体功能障碍和 I 类 HDAC 抑制导致氧化损伤减弱 NOS 活性。根据这些信息，我们建议通过测试我们的新的假设认为，I 类 HDAC 激活通过促进 WM 缺血性损伤的增加来介导 WM 缺血性损伤。氧化应激、损害线粒体功能以及下调 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 相互作用以对年轻和老年 WM 产生缺血后损伤。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招募 NOS；目标2 旨在确定 I 类 HDAC 激活是否直接介导线粒体损伤缺血；目标 3 旨在确定 I 类 HDAC 是否与 miR-331 相互作用以介导缺血性 WM 损伤。总体而言，本项目将揭示 I 类 HDAC 活性在 WM 缺血中的作用损伤，以帮助设计新的疗法，以尽量减少患者的缺血后损伤。