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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.

摘要