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

• 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
• 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' s disease model; Alzheimer' 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

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 阿尔茨海默病和相关痴呆（ADRD）是多因素疾病。为了有效治疗ADRD， 更好地理解导致疾病病因的各种因素是重要的。近年来 增加认识血管对认知障碍和痴呆（VCID）的贡献， ADRD的发展和进展。虽然以前的研究已经检查了多种机制， 虽然细胞外pH值的变化可能导致血管功能障碍，但对细胞外pH值在这一过程中的功能重要性知之甚少。 过程然而，功能性磁共振成像显示，脑酸中毒不仅发生在痴呆症患者中， 也与疾病严重程度呈正相关。在我们的初步研究中，我们进一步表明， 痴呆小鼠模型表现出慢性脑酸中毒。此外，脑酸中毒突出且持续 脑缺血和创伤性脑损伤后，易患老年痴呆症。在 与这些条件下脑pH值降低的普遍性相反，缺乏关于脑酸的知识 血管性痴呆中的信号传导为了填补这一知识空白，本补充申请将采取独特的 角度和重点酸（质子）介导的信号通过GPR4，质子敏感的GPCR存在 脑微血管内皮细胞（BMEC）。使用5XFAD小鼠和新的条件GPR4 敲除小鼠，该应用将确定内皮细胞中GPR4的基因消融是否 在5XFAD痴呆小鼠模型中的认知障碍和神经炎症。以产生更多的见解 痴呆症和大脑pH值，该应用程序将确定5XFAD中大脑pH值的年龄依赖性变化 小鼠此外，本申请将进一步研究所观察到的变化的分子信号传导， 在分离自5XFAD动物的BMEC细胞中进行无偏转录组分析。结果 获得将奠定基础，为未来深入的机制，以及针对这一转化研究 ADRD的新途径。