Mechanistic inquiry of GPR68-mediated neuroprotection against post-stroke deficits and VCID

GPR68 介导的针对中风后缺陷和 VCID 的神经保护作用的机制探究

基本信息

批准号：
10807584
负责人：
Xiangming Zha
金额：
$ 62.71万
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：
2023
资助国家：
美国
起止时间：
2023-09-25 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10807584
关键词：
3-Dimensional Acidosis Acids Acute Acute Brain Injuries Animals Attenuated Behavior assessment Biodistribution Brain Brain Ischemia Cells Chemosensitization Chronic Contralateral Data Dementia Development Disease Disease Progression Drug Kinetics EIF-2alpha Endoplasmic Reticulum Eukaryotic Initiation Factors Exhibits G-Protein-Coupled Receptors GPR68 gene Human Hyperglycemia In Vitro Induction of Apoptosis Injury Intervention Ipsilateral Ischemia Ischemic Brain Injury Ischemic Stroke Knockout Mice Knowledge Location Measures Mediating Middle Cerebral Artery Occlusion Modeling Molecular Mus Neuronal Injury Neurons Outcome Pathway interactions Patients Phosphorylation Phosphotransferases Physiological Process Protein Biosynthesis Proteins Protons Reperfusion Therapy Risk Factors Signal Induction Signal Transduction Site Slice Solid Specificity Stroke Testing Therapeutic Intervention Tissues Vascular Cognitive Impairment brain tissue disability improved in vivo in vivo Model insight middle age neuroprotection neurotoxicity novel novel therapeutic intervention pharmacologic post stroke post stroke dementia protective effect receptor response transcriptome translational potential vascular cognitive impairment and dementia

项目摘要

ABSTRACT Stroke leads to acute brain injury and is one of the leading causes of long-term disabilities, which include the development of vascular cognitive impairment (VCI) and post-stroke dementia. Defining new neuroprotective mechanisms following stroke is essential for alleviating both neuronal injury at acute stage and for protecting against post-stroke VCI and dementia. The most common type of stroke in human patients is ischemic stroke. During ischemia or following reperfusion, brain acidification occurs. Acidosis can have both pro-injury and protective effects. In our previous studies, we found that GPR68, also known as ovarian cancer G protein coupled receptor 1 (OGR1), a proton-sensitive G protein coupled receptor (GPCR), is widely expressed in the brain and mediates acid-induced signaling in brain neurons. Our data further suggest that GPR68 activation protects neurons in acidotic and ischemic conditions. To further our knowledge on GPR68-dependent protection, this application will investigate the molecular mechanism by which GPR68 elicits neuroprotection. Using in vitro and in vivo models, we will determine a novel mechanism by which GPR68 induces unfolded protein response (UPR) in neurons. Further, we will assess the translational potential of pharmacological targeting of GPR68. We will perform long-term behavioral assessment to determine whether GPR68 potentiation offers protection against the development of post-stroke disabilities, including post-stroke VCID. Results obtained from the proposed study will uncover novel protective mechanisms mediating GPR68-mediate neuroprotection and generate critical information for novel therapeutic approaches through targeting GPR68 to alleviate post-stroke dementia.

抽象的中风会导致急性脑损伤，是导致长期残疾的主要原因之一，其中包括血管性认知障碍（VCI）和中风后痴呆的发展。定义新的神经保护剂中风后的机制对于减轻急性期神经元损伤和保护神经元至关重要对抗中风后 VCI 和痴呆症。人类患者中最常见的中风类型是缺血性中风。在缺血期间或再灌注后，大脑会发生酸化。酸中毒可以同时具有促损伤和保护作用。在我们之前的研究中，我们发现GPR68，也称为卵巢癌G蛋白偶联受体 1 (OGR1) 是一种质子敏感的 G 蛋白偶联受体 (GPCR)，在大脑中广泛表达，介导大脑神经元中酸诱导的信号传导。我们的数据进一步表明 GPR68 激活可以保护酸中毒和缺血条件下的神经元。为了加深我们对 GPR68 相关保护的了解，这该应用将研究 GPR68 引起神经保护的分子机制。使用体外和在体内模型中，我们将确定 GPR68 诱导未折叠蛋白反应 (UPR) 的新机制在神经元中。此外，我们将评估 GPR68 药理学靶向的转化潜力。我们将进行长期行为评估以确定 GPR68 增强作用是否能提供针对中风后残疾的发展，包括中风后 VCID。从提议中获得的结果研究将揭示介导 GPR68 介导神经保护的新保护机制，并产生关键的通过靶向 GPR68 缓解中风后痴呆的新治疗方法的信息。