GPR4 in blood brain barrier dysfunction in brain ischemia

GPR4在脑缺血血脑屏障功能障碍中的作用

基本信息

批准号：
10711110
负责人：
Xiangming Zha
金额：
$ 39.13万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
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：
2022-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10711110
关键词：
Ablation Acidosis Acids Address Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Amyloid beta-Protein Amyloid deposition Animals Attenuated Blood - brain barrier anatomy Blood Vessels Blood brain barrier dysfunction Brain Brain Ischemia Breeding Cell Separation Cells Cerebellum Cerebrovascular system Chronic Cognitive deficits Data Databases Dementia Development Disease Disease Progression Electrical Resistance Endothelial Cells Endothelium Etiology Exhibits Foundations Functional Magnetic Resonance Imaging Functional disorder Future G-Protein-Coupled Receptors GPR4 gene Genes Genetic Grant Human Image Impaired cognition In Vitro Inflammatory Intercellular Junctions Ischemia Ischemic Brain Injury Ischemic Stroke Knockout Mice Knowledge Laboratories Life Link Mediating Microglia Modeling Molecular Mus Neuronal Injury Parents Pathway interactions Patients Peripheral Prevalence Process Protons Rho-associated kinase Rodent Severity of illness Signal Transduction Temporal Lobe Testing Therapeutic Time Traumatic Brain Injury Up-Regulation Vascular Cognitive Impairment Vascular Dementia Vascular Diseases age related brain endothelial cell cognitive function cognitive performance experimental study extracellular inhibitor insight mRNA sequencing mouse model neuroinflammation neuron loss novel receptor therapeutic target tool transcriptome transcriptome sequencing translational study vascular cognitive impairment and dementia

项目摘要

ABSTRACT Alzheimer’s disease and related dementias (ADRD) are multifactorial diseases. For efficient treatment of ADRD, a better understanding of various factors leading to disease etiology is important. In recent years, there are increased appreciation of vascular contributions to cognitive impairment and dementia (VCID) in the development and progression of ADRD. While previous studies have examined multiple mechanisms contributing to vascular dysfunction, little is known about the functional important of extracellular pH in this process. However, functional MRI imaging shows that brain acidosis not only occurs in dementia patients but also exhibits positive correlation with disease severity. In our preliminary study, we further showed that a 5XFAD mouse model of dementia exhibited chronic brain acidosis. In addition, brain acidosis is prominent and persistent following ischemia and traumatic brain injury, which predispose the development of dementia later in life. In contrast to the prevalence of brain pH reduction in these conditions, there is a dearth of knowledge on brain acid signaling in vascular dementia. To fill in this gap in knowledge, this Supplement application will take a unique angle and focus on acid (proton)-mediated signaling through GPR4, a proton-sensitive GPCR which is present in brain microvascular endothelial cells (BMEC). Using the 5XFAD mouse and a novel conditional GPR4 knockout mouse, this application will determine whether genetic ablation of GPR4 in endothelium alleviates cognitive impairment and neuroinflammation in the 5XFAD mouse model of dementia. To generate more insights into dementia and brain pH, this application will determine age-dependent changes in brain pH in the 5XFAD mice. Further, this application will further investigate molecular signaling underlying the observed changes and perform an unbiased transcriptome analysis in BMEC cells isolated from the 5XFAD animals. The results obtained will lay the groundwork for future in-depth mechanistic as well as translational studies of targeting this novel pathway in ADRD.

抽象的阿尔茨海默氏病和相关痴呆症（ADRD）是多因素疾病。为了有效治疗ADRD 更好地了解导致病因的各种因素很重要。近年来，有对认知障碍和痴呆（VCID）的血管贡献的欣赏增加了 ADRD的发展和发展。虽然先前的研究已经检查了多种机制有助于血管功能障碍，在此对细胞外pH的功能知之甚少过程。然而，功能性MRI成像表明，脑酸中毒不仅发生在痴呆症患者中，而且发生还表现出与疾病严重程度的正相关。在我们的初步研究中，我们进一步表明了一个5xfad 痴呆症小鼠模型暴露于慢性脑酸中毒。此外，脑酸中毒是突出的，并且持续局部缺血和脑损伤，这种脑损伤易于生命后期的痴呆症的发展。与这些条件下脑pH降低的患病率相反，对脑酸的知识死亡血管痴呆中的信号传导。为了填补知识的差距，此补充申请将采用独特的角度和专注于酸（质子）介导的信号传导，通过GPR4（一种质子敏感的GPCR）在脑微血管内皮细胞（BMEC）中。使用5xFAD鼠标和新颖的条件GPR4 敲除鼠标，该应用将确定内皮中GPR4的遗传消融是否减轻 5xFAD小鼠痴呆模型中的认知障碍和神经炎症。为了产生更多的见解对于痴呆和脑pH，该应用将确定5xFAD中脑pH的年龄变化老鼠。此外，该应用将进一步研究观察到的变化和在从5XFAD动物中分离出的BMEC细胞中进行无偏的转录组分析。结果获得的将为未来的深入机械和转化研究奠定基础 Adrd的新颖道路。