2015 — 2016 |
Zha, Xiangming |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Ogr1 as a Novel Mediator of Acid Signaling in the Brain @ University of South Alabama
? DESCRIPTION (provided by applicant): Acidification of extracellular space occurs in brain ischemia. This acidification is one important contributor to ischemia-induced neuronal injury. Current literature emphasizes an injurious role of acidosis, mediated mostly by the acid-sensing ion channels in ischemia. The current proposal investigates a novel signaling pathway mediated by ovarian cancer G protein-coupled receptor 1 (OGR1), an acid-sensitive G protein coupled receptor. With the OGR1 null mice and organotypic hippocampal slices, we will test the hypothesis that activating the OGR1 pathway attenuates acidosis- and ischemic-induced neuronal injury. The proposed research will uncover an unexpected neuroprotective aspect of acidosis. The results will reveal a biphasic (pro-survival vs. pro-injury) picture of acidosis in neuronal survival, and will be critical for future therapeutic interventions in stroke and other neurological diseases that reduces brain pH.
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0.976 |
2017 — 2021 |
Zha, Xiangming |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuroprotective Role of Ogr1 in Brain Ischemia @ University of South Alabama
PROJECT ABSTRACT 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.
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0.976 |