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.

项目概要血管性认知障碍和痴呆中白质损伤（WMI）机制的研究进展（VCID）由于我们对血管和神经胶质机制的理解存在根本差距而受到阻碍与髓鞘再生失败的发病机制有关，这是 VCID 的一个标志。我们提出了一个高度集成的分析微血管和少突胶质细胞祖细胞 (OPC) 之间的相互作用 VCID发病机制。我们将在机制上将功能失调的反应性与 WM 的炎症联系起来 OPC 对 WMI 的反应中脉管系统对新型血管周围紊乱的影响，这似乎是髓鞘形成的核心 VCID 失败。我们将检验最重要的假设，即白质小动脉功能障碍选择性地建立血管周围 WMI 免受氧化和亚硝化应激的脆弱区域导致与异常 OPC 迁移相关的功能性不成熟白质生态位，增殖和分化为髓鞘少突胶质细胞。这个假设得到了我们的支持最近的研究（Bagi 等人，Ann Neurol 2018；83:142-152）发现选择性受损的血管舒张剂人白质穿通小动脉在类似白质微血管脑损伤（mVBI）中的功能发生髓鞘形成前 OPC 成熟破坏的区域。在这三个目标中，我们将采用从大量 VCID 病例中收集的人类快速尸检大脑的独特集合，其中白质通过死前 MRI 识别高信号 (WMH)。尽管 WMH 广泛应用于临床识别有认知能力下降风险的患者，其病理基础尚不清楚。在目标 1 中，我们将定义白质小动脉胆碱能血管舒张受损、高血管壁之间的机制关系活性氧和氮物种增加产生的剪切应力和 WMI。我们将测试胆碱能血管舒张受损使 WM 穿通小动脉中的内皮细胞暴露于高水平的壁剪切应力，导致活性氧和氮的产生增加在 mVBI 中。在目标 2 中，我们将定义 OPC 血管生态位中的分子扰动，这些扰动有助于 mVBI 中髓鞘形成失败。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。我们将利用几条新数据线来证明新颖性 WM 小动脉和毛细血管水平 OPC 的血管周围损伤反应。在目标 3 中，我们将定义与透明质酸（HA）介导的 WM 功能障碍相关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来定义各种形式的作用 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机械分子解释独特的 OPC 血管过程使衰老的人类白质特别容易受到微血管 WMI 旨在开发促进慢性 WMI 髓鞘再生的疗法。