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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：
10618140
负责人：
Stephen Arthur Back
金额：
$ 67.78万
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618140
关键词：
3-nitrotyrosine Abbreviations Acetylcholine Acids Adhesions Adult Age Years Aging Autopsy Biology Blood Vessels Blood capillaries Blood flow Brain CD44 gene Catabolism Cell Maturation Cerebral Ischemia Cerebrovascular Trauma Cerebrum Cholinergic Agonists Chronic Clinical Cognitive Collection Data Dementia Diameter 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 Penetration Peroxides Physiology Play Predisposition Process Production Proliferating 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 ex vivo perfusion 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 vascular injury 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功能障碍和痴呆的白色损伤机制研究进展由于我们对血管和神经胶质机制的理解存在根本性的差距，与髓鞘再生失败的发病机制有关，髓鞘再生失败是VCID的标志。我们提出了一个高度集成的分析微血管和少突胶质祖细胞（OPC）之间的相互作用， VCID发病机制。我们将机械地将WM的功能失调反应性和炎症联系起来在OPC对髓鞘形成的中枢反应中， VCID失败。我们将检验白色小动脉功能障碍建立了血管周围血管的选择性易受氧化和亚硝化应激的区域，导致与异常OPC迁移相关的功能性发育不良的白色物质龛，增殖和分化成髓鞘少突胶质细胞。这一假设得到了我们的支持。最近的研究（Bagi等人，Ann Neurol 2018; 83：142-152），确定了选择性受损的血管扩张剂类白色物质中人WM穿透小动脉在微血管脑损伤中的作用髓鞘形成前OPCs成熟中断的区域。在这三个目标中，我们将采用从一个大的VCID病例队列中收集了一个独特的人类快速尸检大脑，其中白色物质通过生前MRI鉴定高信号（WMH）。尽管WMH在临床上广泛用于识别有认知能力下降风险的患者，其病理基础定义不清。在目标1中，我们将定义白色小动脉胆碱能血管舒张功能受损、血管壁高由活性氧和氮物质的增加产生的剪切应力和剪切应力。我们将测试胆碱能血管舒张功能受损的假设使WM穿透小动脉中的内皮细胞暴露于高水平的壁剪切应力，其诱导活性氧和氮物质的增加的产生在mVBI中。在目标2中，我们将定义OPC-血管生态位中的分子干扰， mVBI中的髓鞘形成失败。我们将重点关注血管因素在异常OPC迁移中的作用，增殖和成熟。我们将利用几条新的数据线， OPCs在WM小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介导WM功能障碍的血管细胞外基质机制小动脉我们将整合使用小鼠和人类血管的方法，以确定各种形式的血管内皮细胞的作用。 HA在血管炎症、血管完整性丧失和异常白细胞粘附和外渗中的作用穿过血管内皮。我们的首要目标是提供一个机械分子解释对于使衰老的人类白色物质特别容易受到微血管再生，以开发促进慢性髓鞘再生的疗法。