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.

响应RFA-NS-16-021，以解决我们对生物学机制的认识中的一些空白 的常见脑血管疾病和年龄相关的白色物质（WM）疾病， 分子，细胞和脑回路水平，我们建议研究周细胞在WM疾病中的作用， 周细胞特异性动物模型和先进的分子、细胞和神经影像学方法，以及回路水平 分析.据估计，全世界高达45%的痴呆症完全或部分是由于年龄相关的小 脑血管病（SVD）。周细胞是嵌入小血液壁的血管壁细胞 血管，如毛细血管、毛细血管前小动脉和毛细血管后小静脉。在大脑中，它们控制着 神经血管功能，如血脑屏障（BBB）完整性和脑血流（CBF）。周细胞 变性导致BBB破坏和血流动力学反应受损，并且在神经系统中发现。 表现出SVD、WM疾病和认知损害的疾病，例如阿尔茨海默氏病、中风和CADASIL， 缺血性SVD和VCID最常见的遗传原因;然而，周细胞在病理生理学中的作用 SVD和WM疾病在很大程度上是未知的。根据我们在周细胞缺陷血小板中获得的初步数据， 衍生生长因子受体-β（PdgfrβF7/F7）小鼠和已发表的表达TgNotch 3R 169 C小鼠的研究 Notch 3 CADASIL突变体在血管平滑肌细胞和周细胞中的表达，我们假设WM周细胞丢失 导致BBB破坏和CBF减少，引起少突胶质细胞损失、脱髓鞘、轴突损伤， 中枢神经系统回路的连接中断和解体，导致功能缺陷和神经元丢失。 由于目前可用的周细胞缺陷型Pdgfb/Pdgfrβ系和TgNotch 3R 169 C小鼠不是周细胞特异性的， 为了验证我们的假设，我们已经产生了新的周细胞特异性细胞系，如Pdgfrβ-Flp、Cspg 4-FSF-CreER、Cspg 4-FSF-CreER和Cspg 4-FSF-CreER。 iDTR小鼠，并将开发一种新的小鼠品系，其具有可诱导的周细胞消融， Notch 3R 169 C仅在周细胞中突变。我们将使用i）最先进的纵向动态对比增强 局部BBB完整性的磁共振成像（MRI），CBF的动态磁化率对比MRI， 弥散张量成像（DTI）和基于DTI的纤维束成像，用于结构/连接性变化和纤维束追踪 基于连接组学的CNS回路水平分析; ii）行为测试;和iii）免疫组织学， 神经病理学、流式细胞术和电子显微镜组织分析。我们将确定 整体诱导性周细胞消融（20-70%）（AIM 1），前扣带局灶性诱导性周细胞丢失， 皮质边缘环（AIM 2）和周细胞特异性诱导型Notch 3R 169 C表达（AIM 3）对BBB完整性的影响， CBF减少、WM完整性、CNS回路中断和功能缺陷（行为）。我们预计 拟议的研究将有助于更好地了解WM疾病的机制基础， 血管性认知障碍和痴呆，并将建立周细胞作为一个新的关键目标WM疾病。