The National Institute of Neurological Disorders and Stroke (NINDS) is an institute within the National Institutes of Health (NIH) that aims to seek fundamental knowledge about the brain and nervous system to reduce the burden of neurological disease. The Research Project Grant, or R01 grant, is the original and historically oldest grant mechanism used by NIH. The R01 provides support for health-related research and development based on the mission of NIH.
Dr. Zha said this is his first R01 grant, which scored in the second percentile. “The grant will allow us to investigate the signaling mediated by ovarian cancer G protein coupled receptor 1 (OGR1), and whether targeting it may have therapeutic potentials in stroke or in acidosis-incurring disease in general,” he said.
Brain pH is tightly regulated but can fluctuate under both physiological and pathological conditions. Various conditions including seizure, stroke, mitochondrial dysfunction and neurodegenerative diseases all lead to a decrease in extracellular pH, or acidosis. “Given the prevalence of acidosis in disease, determining molecular mechanisms underlying acid signaling may have broad translational value,” Dr. Zha said. “It has been known for decades that acidosis is one key contributing factor to neuronal injury. Paradoxically, a relatively mild acidosis can be protective.”
According to Dr. Zha, a lot of progress has been made on understanding how increased acidity in the brain leads to neuronal injury. This is in part due to the discovery of acid-sensing ion channels (ASICs), which are a group of channels that respond to a reduction in pH. “A series of data, including ours, shows that ASICs are the major postsynaptic proton receptor in brain neurons and are a key mediator of acidosis-induced neuronal injury.”
Dr. Zha said these findings on ASICs have greatly advanced the knowledge of acid signaling, but do not explain the protective effect of acidosis. “In our preliminary studies, we found that OGR1 is widely expressed in the brain,” he said. “In addition, OGR1 mediates acid-induced signaling in hippocampal slices. Our data further suggests that OGR1 mediates a protective pathway in neurons.”
According to Dr. Zha, Dr. James Downey, professor emeritus of physiology at the USA College of Medicine, is an expert in cardiac protection and has provided insightful suggestions on ischemia signaling. “Dr. Thomas Rich, associate professor of pharmacology at the USA College of Medicine, and Dr. Zhi-Gang Xiong, professor of neurobiology at the Morehouse School of Medicine, are co-investigators on the grant,” he said. “Dr. Rich will provide his expertise on imaging of intracellular signaling, while Dr. Xiong will provide knowledge on in-vivo rodent ischemia experiments.”
Dr. Zha said the results obtained from the study will likely uncover novel protective mechanisms in response to pH reduction, and provide potential molecular targets for the design of novel therapeutic approaches to alleviate ischemia-induced brain injury.
To learn more about Dr. Zha’s research, click here.
