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

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.