The role of pericytes in white matter disease

周细胞在白质疾病中的作用

• 批准号: 9762993
• 负责人: Berislav V Zlokovic
• 金额: $ 72.21万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762993
• 关键词: Ablation; Address; Affect; Age; Alzheimer' s Disease; Animal Model; Anterior; Behavior; Biological; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Brain Diseases; CADASIL; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Data; Dementia; Demyelinations; Diffuse; Diffusion Magnetic Resonance Imaging; Electron Microscopy; Exhibits; Flow Cytometry; Functional disorder; Genetic; Hippocampus (Brain); Impaired cognition; Impairment; Injury; Knowledge; Lesion; Magnetic Resonance Imaging; Methods; Microvascular Dysfunction; Molecular; Mus; Mutation; NOTCH3 gene; Oligodendroglia; Pathology; Pericytes; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor beta Receptor; Predisposition; Publishing; Role; Smooth Muscle Myocytes; Stroke; Structure; Testing; Tissues; Vascular Smooth Muscle; White Matter Disease; age related; arteriole; axon injury; base; behavior test; brain cell; cell type; cerebral capillary; contrast enhanced; hemodynamics; inducible gene expression; memory recall; mind control; mutant; nervous system disorder; neuroimaging; neuron loss; neuropathology; neurovascular; novel; postcapillary venule; response; tractography; vascular cognitive impairment and dementia; white matter

In response to the RFA-NS-16-021 to address some of the gaps in our knowledge of the biologic mechanisms of the commonly occurring cerebrovascular disease and age-related white matter (WM) disease at the molecular, cellular and brain circuit level, we propose to study the role of pericytes in WM disease using new pericyte-specific animal models and advanced molecular, cellular and neuroimaging methods, and circuit level analysis. Up to 45% of all dementias worldwide are estimated to be wholly or partly due to age-related small vessel disease (SVD) of the brain. Pericytes are vascular mural cells embedded in the wall of small blood vessels such as capillaries, pre-capillary arterioles, and post-capillary venules. In the brain, they control key neurovascular functions such as blood-brain barrier (BBB) integrity and cerebral blood flow (CBF). Pericyte degeneration leads to BBB breakdown and impaired hemodynamic responses, and is found in neurologic disorders exhibiting SVD, WM disease and cognitive impairment such as Alzheimer's, stroke and CADASIL - the most common genetic cause of ischemic SVD and VCID; yet, the role of pericytes in the pathophysiology of SVD and WM disease is largely not known. Based on our pilot data obtained in pericyte-deficient platelet- derived growth factor receptor-β (PdgfrβF7/F7) mice and published studies in TgNotch3R169C mice expressing Notch3 CADASIL mutant in vascular smooth muscle cells and pericytes, we hypothesize that WM pericyte loss leads to BBB breakdown and CBF reductions causing loss of oligodendrocytes, demyelination, axon damage, disrupted connectivity and disintegration of CNS circuits, which leads to functional deficits and neuron loss. Since currently available pericyte-deficient Pdgfb/Pdgfrβ lines and TgNotch3R169C mice are not pericyte specific, to test our hypothesis we have generated new pericyte-specific lines such as Pdgfrβ-Flp; Cspg4-FSF-CreER; iDTR mice with inducible pericyte ablation, and will develop a new mouse line with inducible expression of Notch3R169C mutation only in pericytes. We will use i) cutting-edge longitudinal dynamic contrast-enhanced magnetic resonance imaging (MRI) of regional BBB integrity, dynamic susceptibility contrast MRI of CBF, diffusion tensor imaging (DTI) and DTI-based tractography for structural/connectivity changes, and tract-tracing based connectomics for CNS circuit level analysis; ii) behavior tests; and iii) immunohistology, neuropathology, flow cytometry, and electron microscopy tissue analyses. We will determine the effects of global inducible pericyte ablation (20-70%) (AIM 1), focal inducible pericyte loss in the anterior cingulum of the corticolimbic ciruit (AIM 2) and pericyte-specific inducible Notch3R169C expression (AIM 3) on BBB integrity, CBF reductions, WM integrity, disruption of CNS circuits and functional deficits (behavior). We expect that the proposed studies will contribute towards better understanding of the mechanistic basis of WM disease in vascular cognitive impairment and dementia, and will establish pericyte as a new key target for WM disease.

为了回应RFA-NS-16-021，以解决我们对生物学机制的知识中的一些差距 通常发生的脑血管疾病和与年龄有关的白质（WM）疾病 分子，细胞和脑电路水平，我们建议使用新的WM疾病研究周细胞的作用 周细胞特异性动物模型以及晚期分子，细胞和神经影像学方法以及电路水平 分析。全球所有痴呆症的最多45％估计是完全或部分归因于年龄相关的小 大脑的血管疾病（SVD）。周细胞是嵌入小血壁的血管壁细胞 毛细血管，毛细血管前小动脉和毛细血管后静脉的血管。在大脑中，他们控制钥匙 神经血管功能，例如血脑屏障（BBB）完整性和脑血流（CBF）。周围 退化导致BBB崩溃和血液动力学反应受损，并在神经系统中发现 表现出SVD，WM疾病和认知障碍的疾病，例如阿尔茨海默氏症，中风和卡达西尔 - 缺血性SVD和VCID的最常见遗传原因；然而，周细胞在病理生理学中的作用 SVD和WM病的疾病在很大程度上尚不清楚。基于我们在周细胞缺乏的血小板中获得的试验数据 衍生的生长因子受体-β（PDGFRβF7/F7）小鼠和在表达的Tgnotch3r169c小鼠中发表的研究 Notch3 Cadasil突变体在血管平滑肌细胞和周细胞中，我们假设WM周细胞丧失 导致BBB崩溃和CBF减少，导致少突胶质细胞的损失，脱髓鞘，轴突损伤， 中枢神经系统电路的连通性和分解破坏，导致功能性缺陷和神经元丧失。 由于当前可用的细节缺陷型PDGFB/PDGFRβ系和TGNOTCH3R169C小鼠不是周细胞的特异性 为了检验我们的假设，我们生成了新的周细胞特异性线，例如PDGFRβ-FLP； CSPG4-FSF-CREER; 具有诱导周细胞消融的IDTR小鼠，将开发新的鼠标线，并具有可诱导表达的 Notch3r169c仅在时期内突变。我们将使用i）尖端的纵向动态对比增强 区域BBB完整性的磁共振成像（MRI），CBF的动态敏感性对比度MRI， 扩散张量成像（DTI）和基于DTI的结构/连通性变化的拖拉片段和轨道追踪 CNS电路级分析的基于连接组； ii）行为测试； iii）免疫组织学， 神经病理学，流式细胞仪和电子显微镜组织分析。我们将确定 全球诱导的周细胞消融（20-70％）（AIM 1），局灶性诱导型周围损失在前毛状 corticolimbic ciruit（AIM 2）和周细胞特异性诱导Notch3r169c表达（AIM 3）在BBB完整性上， CBF降低，WM完整性，中枢神经系统电路的破坏和功能性缺陷（行为）。我们期望 拟议的研究将有助于更好地理解WM疾病的机理基础 血管认知障碍和痴呆症，并将在WM疾病的新关键目标中建立多发性疾病。