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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：
10522141
负责人：
Xiangming Zha
金额：
$ 38.73万
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 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522141
关键词：
3-Dimensional ASIC channel Acidosis Acids Acute Address Adhesions Alteplase Animal Model Anions Attenuated Behavioral Blood Blood - brain barrier anatomy Brain Brain Injuries Brain Ischemia Carbon Dioxide Cell physiology Cells Cerebrovascular system Cerebrum Chloride Channels Chronic Phase Data Disease Drug Kinetics Endothelial Cells Endothelium Epithelial Cells Evans blue stain Exhibits Extravasation FDA approved Functional disorder G-Protein-Coupled Receptors GPR4 gene GPR68 gene Human Impairment In Vitro Inflammatory Intercellular Junctions Intervention Ischemia Ischemic Stroke Knowledge Mediating Mediator of activation protein Microglia Middle Cerebral Artery Occlusion Modeling Molecular Mus Neuronal Injury Neurons Outcome Patients Pattern Performance Peripheral Pharmaceutical Preparations Pharmacology Phase Phenotype Prevalence Process Protons Reperfusion Therapy Research Role Signal Transduction Site Stroke Testing Tight Junctions Tissues Vasodilation blood-brain barrier disruption blood-brain barrier permeabilization brain endothelial cell cell type clinically relevant design disability experimental study extracellular functional outcomes genetic manipulation gut inflammation improved in vitro Model in vivo in vivo Model inhibitor insight ischemic injury liquid chromatography mass spectrometry middle cerebral artery new therapeutic target novel receptor stroke outcome stroke therapy therapeutic target transcriptome transcriptome sequencing

项目摘要

ABSTRACT Brain microvascular endothelial cells (BMEC), tightly connected through tight junctions and adhesions junctions, provide the structural basis for the blood-brain barrier (BBB). In both human patients and animal models, BBB disruption exhibits positive correlation with stroke outcome. Discovering novel mechanisms to protect endothelial barrier integrity will provide important insights into better therapeutic targeting of ischemia-reperfusion-induced neuronal injury. One prevalent process in brain ischemia is the prolonged reduction of brain pH, which implicates protons as an important extracellular signal. In previous studies, most emphasis on brain proton signaling has been on its role in neurons. In contrast, few studies have assessed whether acidosis alters blood-brain barrier integrity, which is one important contributor to ischemia-induced neuronal injury. This application will focus on GPR4, a proton-sensitive G protein-coupled receptor which exhibits abundant expression in BMEC. Using a combination of in vivo and in vitro models, the proposed research will determine whether GPR4 mediates acid signaling in BMEC, and identify its downstream mediator in acidotic and ischemic conditions. With genetic manipulation and pharmacological interventions, we will determine whether deleting or inhibiting GPR4 specifically in endothelial cells attenuates ischemia-induced BMEC dysfunction and protects the brain from ischemia-induced neuronal injury. To better understand the mechanism, the research will analyze downstream signaling and perform unbiased analysis of transcriptome changes from acutely isolated BMEC. Lastly, this study will use the liquid chromatography-mass spectrometry approach to determine the pharmacokinetics of a GPR4 inhibitor in brain and blood tissue. Once successfully accomplished, the study will offer GPR4 inhibition as a novel neuroprotective approach to alleviate ischemia-induced brain injury.

摘要