Acid-sensing mechanism of the novel proton-activated chloride channel and its role in ischemic stroke

Project: Research

Investigators

  • Junhua Yang (PI)

Description

Stroke is the most common fatal neurological disease and a leading cause of serious long-term disability in the United States. However, there is only one FDA-approved drug for ischemic stroke, the tissue plasminogen activator (tPA), which is beneficial to patients only within a few hours of having a stroke. Hence there is an urgent need to identify novel therapeutic targets for treatment of this devastating disease. Tissue acidosis is a hallmark of a variety of neurological diseases including ischemic stroke. Besides the cation-conducting acid-sensing ion channels (ASICs), acid also activates a chloride (Cl-) conductance in a wide range of mammalian cells. Evidence suggest that Cl- influx mediated by the proton-activated Cl- channel and subsequent neuronal swelling is one of the key mechanisms leading to ischemia-evoked neuronal death and tissue injury. However, due to the lack of molecular identity, it was impossible to elucidate the precise contribute of proton-activated Cl- channel to acidotoxicity in ischemic stroke. We recently performed an unbiased RNAi screen and identified a novel 2TM protein, PAC (also known as TMEM206), as essential for proton-activated Cl- channel activity. Strikingly, our preliminary data have shown that knockout of mouse PAC abolished proton-activated Cl- current in neurons and attenuated acid-induced cell death and brain damage after ischemic stroke. The proposed research project will combine molecular biology, electrophysiology, mouse genetics, and in vitro experimental stroke models to elucidate the acid-sensing mechanisms of this novel chloride channel and determine its pathological role and underlying mechanism in ischemic acidotoxicity and stroke. Completion of the proposed study on this novel Cl- channel will shed light on its regulatory mechanisms and pathological function, which may lead to new therapeutic strategies for ischemic stroke and other acidosis-related diseases.
Award amount$135,352.00
Award date01/01/2020
Program typePostdoctoral Fellowship
Award ID20POST35200185
Effective start/end date01/01/202012/31/2021
StatusActive