Brain acidification occurs in excitotoxicity, following disrupted metabolism, and in multiple diseases including ischemia, multiple sclerosis, and traumatic brain injury. Given the prevalence of acidosis in disease, determining molecular mechanisms underlying acid signaling will have broad translational value. It has been known for decades that acidosis is one key contributing factor to neuronal injury. Paradoxically, a relatively mild acidosis can be protective. In recent years, a lot of progress has been made on understanding how acidosis leads to neuronal injury. This is largely due to the discovery of acid-sensing ion channels (ASICs), which are a family of proton gated cation channels. A series of data, including ours, show that ASICs are the major postsynaptic proton receptor in brain neurons, and one key mediator of acidosis-induced neuronal injury. These data on ASICs have greatly advanced our knowledge of acid signaling. However, ASICs do not appear to explain the protective effect of acidosis. In our preliminary studies, we found that ovarian cancer G protein coupled receptor 1 (OGR1), a proton-sensitive G protein coupled receptor (GPCR), is widely expressed in the brain. In addition, OGR1 mediates acid-induced signaling in hippocampal slices. Our data further suggest that OGR1 mediates a protective pathway in acidotic and ischemic conditions. Here, we will use middle cerebral artery occlusion, a widely used rodent model for studying ischemia-induced brain injury, and determine whether OGR1 activation leads to neuroprotection following ischemia. To better understand the mechanism, we will use in vitro cell culture and slice models to determine downstream signaling that mediates the effect of OGR1. Results obtained from the proposed study will uncover novel protective mechanisms mediating extracellular acid signaling, and provide potential molecular targets for the design of novel therapeutic approaches to alleviate ischemia-induced brain injury.

Public Health Relevance

Brain acidification occurs in ischemia and multiple other diseases. This proposal will investigate molecular mechanisms mediating a novel protective pathway in acid signaling. The results from the proposed studies will have broad implications for our understanding of acidosis- and ischemia-induced neuronal injury and translational targeting of proton receptors in alleviating neuronal injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS102495-02
Application #
9542386
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Bosetti, Francesca
Project Start
2017-08-15
Project End
2022-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of South Alabama
Department
Physiology
Type
Schools of Medicine
DUNS #
172750234
City
Mobile
State
AL
Country
United States
Zip Code
36688
Jiang, Yu-Qing; Zha, Xiang-Ming (2017) miR-149 reduces while let-7 elevates ASIC1a expression in vitro. Int J Physiol Pathophysiol Pharmacol 9:147-152