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.

项目摘要脑白质异常预测了血管认知障碍和痴呆的发展（VCID）。在白质异常下，包括脑灌注不足在内的血管机制。但是，导致白质功能障碍和认知表现的机制仍然很差了解限制有效治疗的发展。使用人类验尸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小胶质细胞稳态，内皮细胞（EC）功能障碍，血脑屏障（BBB）崩溃和慢性低度微血管炎症。我们的研究现在提供了令人信服的支持，即小胶质细胞“状态” （丰度/功能）通过与EC的相互作用影响白质异常。我们的新兴数据显示小胶质细胞状态对在空间依赖的微血管脑血流（CBF）降低响应方式。白质和灰质 - 神细胞的批量分析白质小胶质细胞敏感性警告更多与隔室相关多样性的深入调查。进一步我们的新数据表明小胶质细胞可能是微血管张力和血液动力学的关键调节剂。我们将以这项工作为基础检验以下假设：小胶质细胞状态的特定调节剂会影响小胶质细胞 - 微血管EC 稳态以及WM异常和认知缺陷的发展和发展 VCID。我们的跨学科团队（爱丁堡，纽卡斯尔，苏塞克斯（英国））具有神经免疫的专业知识机制，髓磷脂和血管生物学将使动物模型桥接到患者。我们将使用专业空间转录方法，成像方式和计算方法提供对小胶质细胞多样性及其如何影响微血管和白质改变的全面见解在VCID中。将实现以下主要目标：目的1：确定微胶质细胞 - 微血管EC异质性和细胞间交流对于人类VCID的WM异常目的2：确定小胶质细胞状态的特定调节剂是否可以改善小胶质细胞 - 微血管EC 稳态并预防VCID模型中的WM疾病进展目标3：与小胶质细胞 - 微血管相互作用提供功能性见解 VCID模型中的WM疾病进展。这些研究将为定义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的谈话和白质完整性，也与阿尔茨海默氏病有关。目标是确定小说早期热干预的免疫调节靶标可减少认知能力下降。