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

摘要 中风会导致急性脑损伤，是导致长期残疾的主要原因之一，包括 血管认知障碍(VCI)和中风后痴呆的发展。定义新的神经保护 卒中后的机制对减轻急性期神经元损伤和保护至关重要 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。 在缺血或再灌流后，脑组织会发生酸化。酸中毒既有促伤作用，也有 起到保护作用。在我们以往的研究中，我们发现GPR68又称卵巢癌G蛋白偶联 受体1(OGR1)是一种质子敏感的G蛋白偶联受体，在大脑和大脑中广泛表达。 在脑神经元中介导酸诱导的信号传递。我们的数据进一步表明，GPR68的激活保护 在酸性和缺血条件下的神经元。为了进一步加深我们对GPR68依赖保护的了解，这 应用程序将研究GPR68诱导神经保护的分子机制。在体外使用和 在活体模型中，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的药理学靶向的翻译潜力。我们会 执行长期行为评估以确定GPR68增强是否提供保护 卒中后残疾的发展，包括卒中后VCID。从建议的项目中获得的结果 研究将发现新的保护机制，介导GPR68-介导的神经保护并产生关键的 通过靶向GPR68来缓解中风后痴呆的新治疗方法的信息。

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.