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Oligodendrocyte Progenitors and Mechanisms of Human Vascular White Matter Injury

少突胶质细胞祖细胞和人类血管白质损伤的机制

基本信息

批准号：
10394799
负责人：
Stephen Arthur Back
金额：
$ 68.9万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394799
关键词：
3-nitrotyrosine Abbreviations Acetylcholine Acids Adhesions Adult Age-Years Aging Autopsy Biology Blood Vessels Blood capillaries Blood flow Brain Brain Injuries CD44 gene Caliber Catabolism Cell Maturation Cerebral Ischemia Cerebrovascular Trauma Cerebrum Cholinergic Agonists Chronic Clinical Cognitive Collection Data Dementia Diffuse Elderly Endothelial Cells Endothelium Extracellular Matrix Extravasation Failure Fibrinogen Functional disorder Genes Human Hyaluronic Acid Impaired cognition Impairment Individual Inflammation Inflammatory Injury Isoprostanes Lesion Leukocytes Link Lymphocyte Magnetic Resonance Imaging Measures Mediating Microvascular Dysfunction Molecular Mus Muscarinic Acetylcholine Receptor Myelin Natural regeneration Nitric Oxide Nitrogen Oligodendroglia Oxidative Stress Oxygen Pathogenesis Pathologic Patients Peroxides Physiology Play Process Production Recovery Risk Role Site Superoxides Surface Techniques Testing Vascular Cognitive Impairment Vascular Dementia Vascular Diseases Vascular Endothelium Vascular Permeabilities Vasodilation Vasodilator Agents White Matter Hyperintensity aging brain arteriole brain cell cell motility cell type cerebrovascular cholinergic clinical predictors cohort dementia risk endothelial dysfunction gray matter in vitro Model migration mouse model multidisciplinary myelination neuroimaging neuropathology nitrosative stress nonhuman primate novel oligodendrocyte progenitor overexpression oxidative damage remyelination repaired response response to injury shear stress stem cell proliferation stem cells therapy development vascular cognitive impairment and dementia vascular factor vascular inflammation white matter white matter injury

项目摘要

Project Summary Progress to define mechanisms of white matter injury (WMI) in vascular cognitive impairment and dementia (VCID) has been hampered by fundamental gaps in our understanding of the vascular and glial mechanisms related to the pathogenesis of remyelination failure, a hallmark of VCID. We propose a highly integrated analysis of the interplay between microvascular and oligodendrocyte progenitor cell (OPC) contributions to VCID pathogenesis. We will mechanistically link dysfunctional reactivity and inflammation of the WM vasculature to novel perivascular disturbances in OPC responses to WMI that appear central to myelination failure in VCID. We will test the over-riding hypothesis that dysfunction of white matter arterioles establishes selectively vulnerable zones of perivascular WMI from oxidative and nitrosative stress that result in functionally dysmature white matter niches associated with aberrant OPC migration, proliferation and differentiation to myelinating oligodendrocytes. This hypothesis is supported by our recent studies (Bagi et al., Ann Neurol 2018; 83:142-152) that identified selectively impaired vasodilator function of human WM penetrating arterioles in microvascular brain injury (mVBI) in similar white matter regions where disrupted maturation of pre-myelinating OPCs occurred. In all three aims, we will employ a unique collection of human rapid autopsy brains from a large cohort of cases with VCID where white matter hyperintensities (WMHs) were identified by ante-mortem MRI. Although WMHs are widely used clinically to identify patients at risk for cognitive decline, their pathological basis is poorly defined. In aim 1, we will define mechanistic relationships among impaired cholinergic vasodilation of white matter arterioles, high vascular wall shear stress and WMI arising from augmented production of reactive oxygen and nitrogen species. We will test the hypothesis that impaired cholinergic vasodilation exposes endothelial cells in WM penetrating arterioles to a high level of wall shear stress, which induces augmented production of reactive oxygen and nitrogen species in mVBI. In aim 2, we will define molecular disturbances in the OPC-vascular niche that contribute to myelination failure in mVBI. We will focus on the role of vascular factors in aberrant OPC migration, proliferation and maturation. We will capitalize on several new lines of data that demonstrate novel perivascular injury responses of OPCs at the level of WM arterioles and capillaries. In aim 3, we will define vascular extracellular matrix mechanisms related to hyaluronic acid (HA)-mediated dysfunction of WM arterioles. We will integrate approaches using murine and human vessels to define the role of various forms of HA in vascular inflammation, loss of vascular integrity and abnormal leukocyte adhesion and extravasation across the vascular endothelium. Our over-riding objective is to provide a mechanistic molecular explanation for the distinct OPC-vascular processes that render aging human white matter particularly susceptible to microvascular WMI in order to develop therapies that promote remyelination in chronic WMI.

项目摘要血管性认知障碍和痴呆患者脑白质损伤机制的研究进展 (VCID)一直受到我们对血管和神经胶质机制理解上的根本差距的阻碍与VCID的标志之一--再髓鞘衰竭的发病机制有关。我们提出了一个高度集成的微血管和少突胶质祖细胞(OPC)对脑出血的作用分析 VCID发病机制。我们将机械地将WM的功能障碍反应和炎症联系起来 OPC对似乎是髓鞘中枢的WMI反应中新的血管周围障碍的血管系统 VCID失败。我们将检验白质小动脉功能障碍这一压倒一切的假设在氧化和亚硝化应激下选择性地建立血管周围WMI的脆弱区域，导致与异常的OPC迁移相关的功能不成熟的白质壁龛，向髓鞘少突胶质细胞增殖和分化。这一假设得到了我们的最近的研究(Bagi等人，Ann Neurol 2018；83：142-152)发现了选择性受损的血管扩张剂人白质穿透小动脉在类白质微血管脑损伤中的作用髓鞘前OPC成熟受阻的区域。在所有三个目标中，我们都将使用从大量VCID病例中收集独特的人类快速尸检大脑，其中脑白质高信号(WMH)通过死前MRI进行识别。尽管WMH在临床上被广泛用于识别有认知衰退风险的患者，他们的病理基础还没有明确的定义。在目标1中，我们将定义白质小动脉、高管壁胆碱能血管扩张受损的机制研究由于活性氧和氮物种的增加而产生的剪切力和WMI。我们将测试胆碱能血管扩张受损使穿透小动脉的西医内皮细胞暴露于高水平的壁面剪切力，导致活性氧和氮物种的增加产生在mVBI中。在目标2中，我们将定义OPC-血管生态位中有助于 MVBI的髓鞘形成失败。我们将重点介绍血管因素在OPC异常迁移中的作用，增殖和成熟。我们将利用几个新的数据行来展示新奇的 OPC在西微动脉和毛细血管水平的血管周围损伤反应。在目标3中，我们将定义透明质酸(HA)介导的WM功能障碍与血管细胞外基质机制的关系小动脉。我们将结合使用小鼠和人类血管的方法来定义各种形式的透明质酸与血管炎症、血管完整性丧失及白细胞异常黏附和渗出穿过血管内皮细胞。我们最重要的目标是提供一种机械论的分子解释因为独特的OPC-血管突起使人的脑白质特别容易老化微血管WMI，以开发促进慢性WMI重新髓鞘形成的治疗方法。