Modifying endothelial Piezo 1 function to improve brain perfusion in AD/ADRD

修改内皮 Piezo 1 功能以改善 AD/ADRD 患者的脑灌注

基本信息

批准号：
10658645
负责人：
Sean P Marrelli
金额：
$ 62.39万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2023-06-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658645
关键词：
3-Dimensional Acceleration Acute Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid beta-Protein Amyloidosis Biosensor Blood Vessels Blood flow Brain Brain Pathology Calcium Cerebral Amyloid Angiopathy Cerebrovascular Circulation Chronic Cognition Cognitive Data Development Encephalitis Endothelial Cells Endothelium Functional disorder Gene Expression Profile Gene Expression Regulation Gliosis Hyperemia Image Impaired cognition Impairment Inflammation Ion Channel Ion Channel Gating Knock-out Laser Speckle Imaging Learning Macrophage Measures Mediating Membrane Memory Microglia Modeling Mus Mutation Pathology Patients Perfusion Peripheral Piezo 1 ion channel Public Health Regulation Rest Role Signal Transduction Stretching Testing Tg2576 Up-Regulation Vasodilation aged aging brain amyloid pathology arteriole behavior test behavioral study brain endothelial cell brain health cerebral amyloidosis cerebral hypoperfusion cerebrovascular cerebrovascular pathology cognitive performance endothelial dysfunction gain of function hypoperfusion improved in vivo loss of function mouse model new therapeutic target novel novel strategies pharmacologic quantitative imaging recruit resilience response sex therapeutic target two-photon white matter white matter injury

项目摘要

The following proposal is built on our recent novel findings showing a critical role for endothelial Piezo1 in cerebral blood flow (CBF) regulation and brain health. Piezo1 is a mechanosensitive ion channel that gates Ca2+ and Na+ influx in response to membrane stretch or increased shear force. In the peripheral vasculature, endothelial Piezo1 is activated by increased flow/shear and promotes vasodilation through Ca2+-dependent mechanisms. We now provide novel preliminary data demonstrating that selective loss of endothelial Piezo1 promotes a decrease in resting CBF (hypoperfusion), while pharmacological activation of endothelial cell (EC) Piezo1 promotes increased CBF (hyperemia). Our data further show that the consequences of chronic EC Piezo1 loss of function (LOF) include endothelial upregulation of genes associated with inflammation and microglia/macrophage recruitment (scRNAseq), widespread microgliosis, and development of white matter injury. In specific regard to AD/ADRD, beta-amyloid (Ab) peptides (e.g. Ab40, Ab42) have been shown to acutely reduce Piezo1 sensitivity to flow/shear activation. These findings offer the intriguing possibility that conditions of amyloidosis may impair EC Piezo1-mediated CBF regulation. Our preliminary data support this possibility, as we show progressive impairment of EC Piezo1-dependent hyperemia in pre-symptomatic and symptomatic TgAPP mice. Additionally, by analyzing public snRNAseq data from AD and cognitively normal patients, we found a transcriptional signature consistent with reduced flow- and Piezo1-dependent signaling in EC from brain of AD patients. Together, these data suggest that EC Piezo1 is vital for normal CBF regulation and that the dysfunction of EC Piezo1 can exacerbate cerebral hypoperfusion and worsen age and Ab-driven pathology. In the proposed project, we will define how EC Piezo1 LOF contributes to cerebrovascular pathology in aging and amyloidosis and explore the novel strategy of EC Piezo1 gain of function (GOF) as an ameliorative solution. Our overall hypothesis is that EC Piezo1 LOF potentiates aging and Ab-mediated pathology and that EC Piezo1 GOF can restore cerebrovascular function and provide resilience to aging and Ab-mediated cognitive decline. Aim 1 will define how brain- specific EC Piezo1 LOF leads to brain pathology in mouse models of aging and amyloidosis. We will use two TgAPP mouse lines that model different aspects of amyloidosis (Tg2576 and TgSwDI). Aim 2 will leverage the ability to enhance CBF via EC Piezo1 GOF to restore CBF regulation, provide cerebrovascular resilience, and slow progression of aging and Ab-related brain pathology and cognitive decline in mouse models of aging and amyloidosis. We will induce Piezo1 GOF selectively in brain endothelium of young and aged WT mice and in TgAPP mice at pre-symptomatic and symptomatic stages. Completion of Aims 1 and 2 will employ a combination of in vivo measures of CBF and cerebrovascular function, measures of EC Piezo1 channel function, 3D quantitative imaging of white matter tracts, brain and vascular immuno/histochemical analyses, and behavior studies. All studies will be performed in both sexes. If successful, these studies will establish EC Piezo1 as a valuable therapeutic target for enhancing brain perfusion and reducing cognitive decline.

以下建议基于我们最近的新发现，显示内皮 Piezo1 在脑血中的关键作用流量（CBF）调节和大脑健康。 Piezo1 是一种机械敏感离子通道，可响应响应而控制 Ca2+ 和 Na+ 的流入膜拉伸或增加剪切力。在外周血管系统中，内皮 Piezo1 被激活流动/剪切并通过 Ca2+ 依赖性机制促进血管舒张。我们现在提供新颖的初步数据证明内皮 Piezo1 的选择性丧失会促进静息 CBF 的减少（灌注不足），而内皮细胞 (EC) Piezo1 的药理激活可促进 CBF 增加（充血）。我们的数据进一步显示慢性 EC Piezo1 功能丧失 (LOF) 的后果包括相关基因的内皮上调炎症和小胶质细胞/巨噬细胞募集 (scRNAseq)、广泛的小胶质细胞增生和白质损伤。特别是对于 AD/ADRD，β-淀粉样蛋白 (Ab) 肽（例如 Ab40、Ab42）已被证明可以急剧降低 Piezo1 对流动/剪切激活的敏感性。这些发现提供了一个有趣的可能性，即淀粉样变性可能会损害 EC Piezo1 介导的 CBF 调节。我们的初步数据支持这种可能性，因为我们显示症状前和症状 TgAPP 小鼠中 EC Piezo1 依赖性充血。另外，通过分析公众来自 AD 和认知正常患者的 snRNAseq 数据，我们发现了与减少的转录特征一致的转录特征 AD 患者大脑中 EC 中的流和压电 1 依赖性信号传导。总之，这些数据表明 EC Piezo1 至关重要正常的 CBF 调节和 EC Piezo1 的功能障碍会加剧脑灌注不足并恶化年龄和抗体驱动的病理学。在拟议的项目中，我们将定义 EC Piezo1 LOF 如何对衰老和衰老过程中的脑血管病理学做出贡献淀粉样变性并探索 EC Piezo1 功能增益 (GOF) 作为改善解决方案的新策略。我们的整体假设 EC Piezo1 LOF 会增强衰老和 Ab 介导的病理，而 EC Piezo1 GOF 可以恢复脑血管功能并提供抵御衰老和抗体介导的认知能力下降的能力。目标 1 将定义大脑如何特定的 EC Piezo1 LOF 会导致衰老和淀粉样变性小鼠模型中的脑部病理学变化。我们将使用两个 TgAPP 鼠标模拟淀粉样变性不同方面的细胞系（Tg2576 和 TgSwDI）。目标 2 将利用增强 CBF 的能力 EC Piezo1 GOF 可恢复 CBF 调节，提供脑血管弹性，并减缓衰老和抗体相关的进展衰老和淀粉样变性小鼠模型的脑病理学和认知能力下降。我们将选择性诱导 Piezo1 GOF 年轻和老年 WT 小鼠以及 TgAPP 小鼠在症状前和症状阶段的脑内皮。完成目标 1 和 2 将采用 CBF 和脑血管功能的体内测量相结合，测量 EC Piezo1 通道功能、白质束 3D 定量成像、脑和血管免疫/组织化学分析和行为研究。所有研究都将在男女中进行。如果成功，这些研究将建立 EC Piezo1 作为增强大脑灌注和减少认知能力下降的重要治疗靶点。