Ischemic stroke is a leading cause of death and long-term disability. Current drug treatment is limited to tPA, which has a low success rate and potentially severe side effects. Acidosis is a common feature of neurological disorders such as brain ischemia, and it has been shown to play a critical role in stroke. The mechanisms, however, remained elusive. The discovery that protons activate a distinct family of cation channels, the acid-sensing ion channels (ASICs), has shed new light on acid-signaling and acidosis-mediated brain injury. The studies in our laboratories in the past 10 years have provided convincing evidence suggesting that activation of ASIC1a contributes markedly to acidosis-mediated ischemic brain injury. Following our initial report, others have demonstrated an important role for ASIC1a activation in spinal cord injury, traumatic brain injury, and axon degeneration. Thus, ASIC1a represents a novel therapeutic target. Despite its well-established role in neurological disorders, the detailed mechanisms underlying ASIC1a-mediated neuronal injury in stroke remain unclear. We now have strong evidence suggesting that, besides the well-documented Ca2+ toxicity, a combination of increased ASIC1a surface expression, Zn2+ toxicity, and an ion conducting independent cell death pathway participate in ASIC-mediated neuronal injury in ischemia. The objective of this application is to investigate the detailed molecular mechanisms and pathways underlying ASIC-mediated neuronal injury. Given the limitations of currently available pharmacological inhibitors that target these channels, e.g. the non-specificity of amiloride and large molecule nature of PcTX1, the proposed studies may disclose novel and alternative therapeutic strategies for ischemic brain injury.
Stroke is a leading cause of mortality and morbidity, yet there is no effective treatment. This proposal focuses on ASIC1a, one major contributor to ischemic brain injury, and investigates the molecular mechanisms underlying ASIC1a-mediated neuronal injury. Results obtained from these studies may lead to novel and effective therapeutic strategies for stroke intervention.
|Huang, Yan; Leng, Tian-Dong; Inoue, Koichi et al. (2018) TRPM7 channels play a role in high glucose-induced endoplasmic reticulum stress and neuronal cell apoptosis. J Biol Chem 293:14393-14406|
|Zhou, Ren-Peng; Leng, Tian-Dong; Yang, Tao et al. (2018) Acute Ethanol Exposure Promotes Autophagy-Lysosome Pathway-Dependent ASIC1a Protein Degradation and Protects Against Acidosis-Induced Neurotoxicity. Mol Neurobiol :|