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Role of Microglia in Cerebral Small Vessel Disease (CSVD)/Vascular Cognitive Impairment (VCI)

小胶质细胞在脑小血管病 (CSVD)/血管认知障碍 (VCI) 中的作用

基本信息

批准号：
10662565
负责人：
JONATHAN R WEINSTEIN
金额：
$ 60.53万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662565
关键词：
Affect Age Astrocytes Attenuated Axon Biological Markers Brain Brain imaging Cell Lineage Cell Separation Cells Cerebral Ischemia Cerebral small vessel disease Cerebrovascular Disorders Cerebrovascular system Cholesterol Chronic Clinical Cognitive Cognitive deficits Collaborations Complement Complex Corpus Callosum Data Data Set Dementia Diagnostic Diet Diffuse Diffusion Magnetic Resonance Imaging Disease Disease Progression Elements Endothelial Cells Exhibits Functional disorder Gene Expression Genes Genetic Goals Human Image Immune Impaired cognition Impairment Infiltration Inflammation Injury Ischemia Ischemic Brain Injury Knowledge Laboratories Laser Speckle Imaging Learning Leukoencephalopathy LoxP-flanked allele Macrophage Macrophage Colony-Stimulating Factor Receptor Magnetic Resonance Imaging Mediator Memory Microglia Modality Modeling Molecular Target Monitor Mus Myelogenous Myeloid Cells Nature Neurocognition Neuroimmune Neurologic Oligodendroglia Oncogenes Outcome Outcome Assessment Pathogenesis Pathologic Pathology Pattern Peripheral Pharmacotherapy Phenotype Population Positron-Emission Tomography Process Radiology Specialty Receptor Signaling Recovery Rest Rodent Rodent Model Role Series Signal Transduction TGFB1 gene Tamoxifen Therapeutic Therapeutic Intervention Time Tissues Transforming Growth Factors Transgenic Mice Universities Vascular Cognitive Impairment Vascular Dementia antagonist attenuation cell type cerebrovascular clinically relevant cognitive testing critical period genetic approach glial activation gray matter imaging study improved in vivo knock-down longitudinal positron emission tomography mouse model neurobehavioral neuroimaging neuroinflammation neurovascular new therapeutic target novel novel marker optical imaging overexpression pharmacologic prevent radioligand radiotracer response scale up sensory stimulus single-cell RNA sequencing tractography transcriptome transcriptomics two-photon uptake vascular cognitive impairment and dementia white matter white matter injury

项目摘要

PROJECT SUMMARY: Microglia, the brain’s resident immune cells, are implicated in the pathophysiology of chronic ischemic cerebral small vessel disease (CSVD) and vascular cognitive impairment (VCI), a clinically important cause of dementia that preferentially affects white matter (WM). Colony stimulating factor 1 receptor (CSF1R) is a key regulator of myeloid lineage cells. Genetic loss of CSF1R blocks the normal population of resident microglia and systemic treatment with CSF1R antagonists such as PLX5622 results in a marked depletion of microglia in the CNS. Here we propose to evaluate the role of microglia and CSF1R signaling in a novel rodent model of CSVD/VCI developed in the laboratory of our colleague Dr. Edith Hamel (McGill University). Mice overexpressing transforming growth factor-beta1 (TGFOE) and fed a high cholesterol diet (HCD) display impaired cerebrovascular reactivity, diffuse leukoencephalopathy, and cognitive dysfunction that resembles human CSVD/VCI. We will first assess effects of TGFOE and HCD on regional and cell type specific gene expression in microglia and other myeloid cells using single cell RNA sequencing. Next we will determine if treatment with PLX5622 influences neurological, neuroimaging, and/or neurovascular outcomes in TGFOE mice (+/-HCD). We will assess longitudinal WM integrity outcomes using state-of- the-art 14 Tesla MRI with diffusion tensor imaging (DTI) and quantitative tractography. We will also use sophisticated assessments of resting-state functional connectivity (optical imaging of intrinsic signals) and neurocognition. Furthermore, we will perform longitudinal 2-photon brain imaging studies to track changes in the cerebrovasculature during critical periods of CSVD/ VCI disease initiation and progression. We will confirm the microglia-specific nature of our findings using an orthogonal genetic approach by crossing TGFOE mice with a Csf1rflox/flox : HexbCreERT2 bigenic line that exhibits stable, microglia-specific knockdown of Csf1r. We will then feed the trigenic TGFOE : Csf1rflox/flox : HexbCreERT2 line HCD and carry out the same comprehensive set of longitudinal parameters described above. We anticipate that both pharmacologic depletion of microglia and genetic deletion of CSF1R signaling specifically in microglia will attenuate WM inflammation and injury and result in improvement in multiple outcome parameters. In aim 3 we will collaborate with our colleagues in Radiology to use a novel CSF1R radioligand to carry out longitudinal positron emission tomography (PET) on TGFOE mice (+/-HCD) at multiple time points during disease initiation and progression. This will provide critical information on temporal and spatial in vivo expression patterns of CSF1R in the context of CSVD/VCI and generate foundational data for a novel biomarker for neuroinflammation that can be readily scaled up from mouse to humans. Overall, this microglia- and CSF1R signaling-targeted, WM-centric approach will provide important mechanistic information on the pathogenesis of ischemic WM injury in CSVD/VCI and elucidate new potential diagnostic and therapeutic approaches.

项目概述：小胶质细胞，大脑的常驻免疫细胞，涉及的病理生理