Oligodendrocyte Progenitor Cell Response to White Matter Stroke

少突胶质细胞祖细胞对白质中风的反应

基本信息

批准号：
10231953
负责人：
Natalie Melinda Shih
金额：
$ 4.09万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231953
关键词：
Acute Adult Area Astrocytes Axon Bioinformatics Blood Vessels Brain CRISPR/Cas technology Candidate Disease Gene Cell Death Cell Differentiation process Cells Cellular biology Cerebrum Chronic Chronic Phase Clinical Clinical Research Cognitive deficits Corpus Callosum Cre-LoxP Dementia Diagnosis Diffuse Electron Microscopy Event Genes Genetic Recombination Goals Human In Vitro Infarction Inflammatory Injury Investigation Ischemic Stroke Lesion Maps Measurable Measures Mediating Membrane Modeling Molecular Molecular Target Motor Cortex Multiple Sclerosis Neurologic Neurologic Deficit Neurons Oligodendroglia Outcome Outcome Measure Process Progressive Disease Proliferating Recovery Recovery of Function Regulator Genes Rehabilitation therapy Role Site Stroke Survival Rate System Tamoxifen Testing Therapeutic Time Tissues Transgenic Organisms Vascular Dementia Vascular Diseases Viral White Matter Disease Work behavioral outcome clinically relevant cognitive task deep sequencing differential expression disability genetic manipulation in vivo innovation interest knockout gene loss of function molecular domain morphogens motor control motor deficit mouse model myelination new therapeutic target novel oligodendrocyte precursor oligodendrocyte progenitor post stroke preclinical study precursor cell relating to nervous system remyelination repaired response stem cell function stem cells stroke model therapy development white matter white matter injury

项目摘要

Project Summary/Abstract White matter stroke is a progressive vascular disease that leads to neurological deficits and can cause dementia. It produces an area of cell death and axonal disruption (the “infarct”) and induces a response of reactive astrocytes and oligodendrocyte precursors cells. In 70% of clinical studies, white matter strokes expand from preexisting lesions into adjacent white matter (the “peri-infarct” region) further damaging and disrupting neuronal connections, causing substantial disability. Currently, what is largely known about white matter repair is derived from studies in non-stroke injuries of white matter such as multiple sclerosis (MS). Limited remyelination occurs in MS through an oligodendrocyte progenitor cell (OPC) response in which OPCs proliferate, differentiate into oligodendrocytes, and remyelinate axons. OPCs proliferate in the peri-infarct region in white matter stroke, but unlike in MS, they do not appear to mature into myelinating oligodendrocytes. This study will utilize a recently developed mouse model of diffuse white matter stroke that produces progressive damage from the small blood vessels in the corpus callosum. This model produces a larger lesion and more closely mimics advanced, chronic stages of human white matter stroke. In aim 1, I will map the OPC response and myelination events after white matter stroke and determine cell fate outcomes of OPCs using novel viral and transgenic approaches. In aim 2, I will determine the role of OPC differentiation induced by candidate genes in white matter repair in vivo. These genes were identified to be highly altered in stroke-induced OPCs as well as to promote OPC differentiation in vitro. The outcome of this work will be to identify novel molecular targets for neural repair and functional recovery in white matter stroke.

项目摘要/摘要白质中风是一种进行性血管疾病，会导致神经系统缺陷并可能引起痴呆症。它会产生细胞死亡和轴突破坏区域（“梗死”），并引起反应性的响应星形胶质细胞和少突胶质细胞前体细胞。在70％的临床研究中，白质中风从预先存在病变成相邻的白质（“围场”区域）进一步破坏并破坏神经元连接，导致实质性残疾。目前，关于白质维修的知名度很大从对多发性硬化症（MS）等白质的非冲程损伤的研究。有限的再髓情况发生在MS中通过少突胶质细胞祖细胞（OPC）反应，其中OPC扩散，分化为 OPC在白质中风中侵略区域中扩散，但与MS不同，它们似乎没有成熟到髓鞘的少突胶质细胞中。这项研究将利用最近开发的小鼠模型的弥漫性白质中风模型，从小血会产生渐进式损害 call体中的船只。该模型会产生更大的病变，更紧密地模拟高级，慢性人类白质中风的阶段。在AIM 1中，我将在白色之后绘制OPC响应和髓鞘形式物质中风并使用新型病毒和转基因方法确定OPC的细胞脂肪结果。在AIM 2中，我将确定候选基因在体内诱导的OPC分化在白质修复中的作用。这些在中风诱导的OPC中，基因被确定为高度改变，并促进OPC分化体外。这项工作的结果将是确定用于神经修复和功能恢复的新分子靶标在白质中风。