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Investigating the cause of cerebral blood flow reductions in a mouse model of frontotemporal dementia

探讨额颞叶痴呆小鼠模型脑血流量减少的原因

基本信息

批准号：
10525598
负责人：
Oliver Bracko
金额：
$ 41.08万
依托单位：
UNIVERSITY OF MIAMI CORAL GABLES
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：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10525598
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease model Antibodies Behavioral Assay Blood - brain barrier anatomy Blood Cells Blood Vessels Blood capillaries Blood flow Candidate Disease Gene Cell surface Cells Cerebrovascular Circulation Characteristics Cognitive deficits Data Data Set Databases Dementia Development Disease Endothelial Cells Endothelium Fluorescence Frontotemporal Dementia Functional Imaging Functional disorder Gene Proteins Grant Image Imaging Device Impaired cognition Impairment Individual Inflammation Label Leukocytes Light Link Measures Membrane Microcirculation Microglia Microvascular Dysfunction Modeling Molecular Molecular Abnormality Mus Nerve Degeneration Neurodegenerative Disorders Neurons Obstruction Oxidative Stress PGRN gene Pathologic Pathology Pathway Analysis Pathway interactions Patients Pericytes Pharmaceutical Preparations Prefrontal Cortex Protein Analysis Proteomics Reporter Resolution Role Severities Short-Term Memory Site Symptoms Thinness Tissues Wild Type Mouse Work cell type constriction density excitotoxicity experimental study fluorescence imaging imaging approach improved in vivo in vivo Model in vivo imaging insight loss of function mutation mouse model multiphoton imaging multiple omics neurovascular unit neutrophil new therapeutic target novel novel therapeutic intervention novel therapeutics protein degradation transcriptome transcriptome sequencing transcriptomics two-photon vascular contributions vascular inflammation

项目摘要

Summary: Substantial reductions in brain blood flow are found in patients and mouse models of neurodegenerative diseases, including frontotemporal dementia (FTD). These blood flow reductions likely contribute to disease symptoms and progression, but the mechanism remains unknown. Recently, two new mechanisms contributing to brain blood flow reductions in Alzheimer's disease were proposed. Interestingly, both capillary stalling and pericyte constriction are associated with microvasculature dysfunction. In preliminary experiments, the PI has shown that capillary stalling found in Alzheimer's disease mice, also occurs in Progranulin (PGRN) deficient mice, a model for FTD. Thus, the project proposed here will investigate the contribution of stalled blood flow and pericyte constriction in capillaries to brain blood flow reductions. Further, this project aims to elucidate the mechanism behind these phenomena using transcriptome analyses and cell-surface proteomics of microvessels from PGRN-deficient mice. The pathology and region predicted to suffer from blood flow reductions in the PGRN deficient mice is the prefrontal cortex, which can be readily studied with the two-photon excited fluorescence imaging tools used previously by the PI. Preliminary data suggests that PRGN-deficient mice display increased capillary stalling caused by white blood cells adhered to the endothelium. For Aim 1, we will use high-resolution, multiphoton, in vivo imaging approaches to structurally and functionally determine blood flow rates in individual capillaries, measure capillary stalling and pericyte constriction, and their interplay. This data will identify the cause of brain blood flow reduction associated with FTD. Aim 2 will elucidate the molecular mechanism linking vascular inflammation to brain blood flow reductions in PGRN-deficient mice by using transcriptomic and cell-surface proteomics to profile microvessels. These experiments will generate two datasets that will allow us to pinpoint molecular aberrations in microvessels of PGRN deficient mice. The data will also shed light on the role of vascular inflammation and vascular obstructions contributing to blood flow reductions. Selected genes and proteins identified in these screens will be independently confirmed and later further analyzed by functional in vivo multiphoton imaging, labeling antibodies, inhibiting drugs, and/or cell-type-specific mouse models. We predict that candidate genes and proteins will be involved in vascular inflammation and associated with oxidative stress, blood-brain barrier breakdown, protein degradation, and lysosomal dysfunction. The idea of capillary stalling is new, and - if confirmed -, could represent a mechanism contributing to brain blood flow reductions in neurodegenerative disease in general, and not just specifically to FTD. If correct, novel therapeutic strategies targeting microvascular inflammation could be developed to improve brain blood flow in patients with FTD and possibly in other neurogenerative diseases with reductions in brain blood flow.

摘要：在患者和小鼠模型中发现脑血流量显著减少