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Altered microglia states and microglia-endothelial cell axis in relation to white matter disease progression in VCID

VCID 中小胶质细胞状态和小胶质细胞内皮细胞轴的改变与白质疾病进展相关

基本信息

批准号：
10738860
负责人：
Jill H Fowler
金额：
$ 54.72万
依托单位：
UNIVERSITY OF EDINBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-18 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10738860
关键词：
Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease risk Animal Model Animals Attenuated Autopsy Autoradiography Behavioral Biology Blood - brain barrier anatomy Blood Vessels Blood brain barrier dysfunction Brain Brain Injuries CSF1R gene Cells Cerebrovascular Circulation Cerebrum Chronic Clinical Cognition Cognitive Cognitive deficits Data Dementia Development Diagnosis Disease Progression Endothelial Cells Fluorescence Foundations Functional disorder Genetic Goals Heterogeneity Homeostasis Human Image Imaging Device Immune Impaired cognition Impairment In Situ In Situ Hybridization Inflammation Investigation Knock-out Lead Link Magnetic Resonance Imaging Mediating Microglia Modeling Molecular Monitor Mus Myelin Neuroimmunomodulation Nuclear Pathology Patients Phenotype Population Positron-Emission Tomography Proteins RNA Reporter Research Signal Transduction Small Nuclear RNA TREM2 gene Testing Therapeutic Intervention Time Tissues Vascular Endothelial Cell Visualization White Matter Disease Work aging brain cerebral hypoperfusion cerebrovascular clinically relevant cognitive ability cognitive performance cohort disability effective therapy gray matter hemodynamics imaging modality immunomodulatory therapies immunoregulation improved in vivo insight intercellular communication mouse model neuroimaging novel pharmacologic post stroke pre-clinical prevent programs prospective radiotracer resilience single-cell RNA sequencing stroke cognitive outcome therapy development tool transcriptomics translation to humans two photon microscopy vascular cognitive impairment and dementia vascular inflammation white matter white matter damage

项目摘要

PROJECT SUMMARY Cerebral white matter abnormalities predict the development of vascular cognitive impairment and dementia (VCID). Vascular mechanisms, including cerebral hypoperfusion, underly white matter abnormalities. However, the mechanisms leading to white matter dysfunction and cognitive performance remain poorly understood limiting the development of effective treatments. Using human post-mortem tissues and studies in animal models, we have shown that key mechanisms that damage white matter include disruption of microglia homeostasis, endothelial cell (EC) dysfunction, blood brain barrier (BBB) breakdown and chronic low-grade microvascular inflammation. Our studies now provide compelling support that microglia ‘state’ (abundance/function) influence white matter abnormalities via interactions with ECs. Our emerging data also show microglia states respond to reduced microvascular cerebral blood flow (CBF) in a spatially-dependent manner. Bulk analysis of white matter and grey matter-microglia implicates white matter microglial sensitivity warranting more in-depth investigation of compartment-related diversity. Further our novel data indicate microglia may be critical regulators of microvascular tone and hemodynamics. We will build on this work to test the hypothesis that specific regulators of microglia state influence microglia-microvascular EC homeostasis and the development and progression of WM abnormalities and cognitive deficits in VCID. Our cross-disciplinary team (Edinburgh, Newcastle, Sussex (UK)) with expertise in neuroimmune mechanisms, myelin and vascular biology will bridge animal model to patient. We will use specialised spatial transcriptomic approaches, imaging modalities and computational approaches to provide a comprehensive insight to the microglial diversity and how it affects microvascular and white matter alterations in VCID. The following key aims would be undertaken: Aim 1: To identify microglia-microvascular EC heterogeneity and intercellular communication in relation to WM abnormalities in human VCID Aim 2: To determine if specific regulators of microglia state can improve microglia -microvascular EC homeostasis and prevent WM disease progression in a model of VCID Aim 3: To provide functional insight to microglia-microvascular interactions, in real time, in relation to WM disease progression in a model of VCID. These studies will provide a critical foundation to define how microglia state influences microglia-EC cross talk and white matter integrity in VCID, also of relevance to Alzheimer’s disease. The goal is to identify novel immunomodulatory targets for early therapeutic intervention to attenuate cognitive decline.

项目总结脑白质异常可预测血管性认知障碍和痴呆的发展 (VCID)。血管机制，包括脑低灌注、脑白质异常。然而，导致白质功能障碍和认知功能障碍的机制仍然很差。了解限制了有效治疗方法的发展。利用人类死后组织和研究在动物模型中，我们已经表明，损害白质的关键机制包括破坏脑白质小胶质细胞稳态、内皮细胞功能障碍、血脑屏障破坏与慢性轻度微血管炎症。我们的研究现在提供了令人信服的支持，即小胶质细胞的状态 (丰度/功能)通过与内皮细胞的相互作用影响白质异常。我们的新兴数据也显示小胶质细胞状态对空间依赖的微血管脑血流量(CBF)减少的反应举止。白质和灰质-小胶质细胞的体积分析暗示白质小胶质细胞的敏感性需要更深入地调查与舱室相关的多样性。此外，我们的新数据表明小胶质细胞可能是微血管张力和血流动力学的重要调节细胞。我们将在这项工作的基础上继续努力检验小胶质细胞状态特异性调节剂影响小胶质细胞-微血管内皮细胞的假说脑内稳态与WM异常及认知功能障碍的发生发展 VCID。我们的跨学科团队(爱丁堡、纽卡斯尔、苏塞克斯(英国))在神经免疫方面拥有专业知识机制、髓鞘和血管生物学将架起动物模型与患者之间的桥梁。我们将使用专业的空间转录方法，成像模式和计算方法，以提供全面了解小胶质细胞的多样性及其对微血管和白质改变的影响在VCID中。将实现以下主要目标：目的1：鉴定小胶质细胞-微血管内皮细胞异质性及其与细胞间通讯的关系人类VCID中的WM异常目的2：确定特定的小胶质细胞状态调节剂是否能改善小胶质细胞-微血管内皮细胞 VCID模型中的动态平衡和预防西医疾病进展目的3：实时了解小胶质细胞与微血管的相互作用。 VCID模型中的西医疾病进展。这些研究将为确定小胶质细胞状态如何影响小胶质细胞-EC交叉提供关键基础 VCID患者的谈话和白质完整性，也与阿尔茨海默病有关。我们的目标是识别小说早期治疗干预以减轻认知功能衰退的免疫调节靶点。