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Brain capillary Piezo1 ion channels and blood flow regulation in Alzheimer’s Disease

阿尔茨海默病中的脑毛细血管 Piezo1 离子通道和血流调节

基本信息

批准号：
10662664
负责人：
Oliver Bracko
金额：
$ 24.21万
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：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662664
关键词：
Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid beta-Protein Architecture Autopsy Blood Blood - brain barrier anatomy Blood Vessels Blood capillaries Blood flow Capillary Endothelial Cell Cell Line Cephalic Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cognitive deficits Data Disease Disease Progression Electrophysiology (science)Embryo Endothelial Cells Endothelium Esthesia Exposure to Foundations Functional disorder Future Genetic Health Image Impairment Ion Channel Life Link Maintenance Measures Mechanics Memory impairment Metabolic Metabolism Molecular Molecular Analysis Mus Neurodegenerative Disorders Neurons Obstruction Patients Pericytes Piezo 1 ion channel Play Probability Proteins Regulation Resolution Risk Factors Role Signal Transduction Stimulus Techniques Testing Three-Dimensional Image Time Translating Western Blotting Wild Type Mouse Work blood-brain barrier permeabilization capillary bed cerebral capillary cerebrovascular constriction end of life endothelial dysfunction flexibility force sensor hemodynamics improved in vivo in vivo imaging innovation insight mechanical force mechanotransduction mouse model neuron loss novel novel therapeutic intervention patch clamp pharmacologic sensor shear stress transcriptome sequencing two photon microscopy two-photon vascular contributions vascular inflammation

项目摘要

Summary: Brain capillary Piezo1 ion channels and blood flow regulation in Alzheimer’s Disease Brain capillaries are the smallest blood vessels in the brain and are crucial in sensing the metabolic needs of active neurons and responding to these needs by supplying more blood. Notably, this function is impaired during neurodegenerative diseases such as Alzheimer’s disease. Not only that capillary sensing is impaired during Alzheimer’s disease, vascular stiffness and complete disruption of capillary blood flow, referred to as capillary stalling, have been observed in mouse models of Alzheimer’s disease. Given that capillary stalling disrupts the hemodynamic forces that capillaries are exposed to, it is important to understand whether Alzheimer’s disease associates with altered mechano-sensing abilities. We recently discovered that the protein Piezo1 is a mechanosensor in brain capillaries. Here, we test the overall hypothesis that altered Piezo1 channel activity is involved in the reduction of brain blood flow in Alzheimer’s disease. We further speculate that tuning Piezo1 activity will improve cerebral blood flow. We will investigate the contribution of endothelial Piezo1 channels to capillary stalling and blood flow reductions in a mouse model of Alzheimer’s disease. Using capillary endothelial cells from wild-type and Alzheimer’s disease mice, we will employ innovative electrophysiological and molecular approaches to assess whether Piezo1 ion channel expression and function are altered during Alzheimer’s disease. In the second aim, we will utilize in vivo high-resolution, two-photon microscopy to investigate capillary stalling and blood flow changes in Alzheimer’s disease mice while pharmacologically manipulating Piezo1 channels. This novel work could lead to new therapeutic strategies not previously tested.

概括：阿尔茨海默病中的脑毛细血管 Piezo1 离子通道和血流调节脑毛细血管是大脑中最小的血管，对于感知新陈代谢的需求至关重要活跃的神经元并通过供应更多的血液来响应这些需求。值得注意的是，该功能在神经退行性疾病，例如阿尔茨海默病。不仅毛细管感应在阿尔茨海默病，血管僵硬和毛细血管血流完全破坏，称为毛细血管在阿尔茨海默病小鼠模型中观察到了停滞。鉴于毛细管失速会扰乱毛细血管所承受的血流动力学力，了解阿尔茨海默病是否与改变机械感应能力的人有关。我们最近发现蛋白质 Piezo1 是一种脑毛细血管中的机械传感器。在这里，我们测试了改变 Piezo1 通道活动的总体假设参与阿尔茨海默病中脑血流量的减少。我们进一步推测调整 Piezo1 活动会改善脑血流量。我们将研究内皮 Piezo1 通道对阿尔茨海默病小鼠模型中毛细血管停滞和血流量减少。使用毛细血管内皮细胞来自野生型和阿尔茨海默病小鼠的细胞，我们将采用创新的电生理学和分子学方法评估 Piezo1 离子通道表达和功能在阿尔茨海默病期间是否发生改变的方法疾病。在第二个目标中，我们将利用体内高分辨率双光子显微镜来研究毛细血管药物操纵 Piezo1 时阿尔茨海默病小鼠的停滞和血流变化渠道。这项新颖的工作可能会带来以前未测试过的新治疗策略。