The recent discovery of acid sensing ion channels (ASICs) as proton receptors in brain, the near universal presence of ASIC currents in neurons, their role in learning/memory, synaptic morphology (of dendritic spines) as well as their pivotal roles in neurological diseases (Ischemia, epilepsy, multiple sclerosis, spinal cord injury) makes the understanding of ASICs of high importance. But remarkably little is known of their physiological functions. For this reason, the proposed study aims to identify and characterize cell signaling pathways activated by ASICIa, a novel member of this proton-gated cation channel family. We hypothesize that ASICIa protein expression and channel activation will activate distinct signal transduction pathways in physiological and pathological conditions. The results of our preliminary high throughput quantitative proteomic analyses of ASICIa-expressing CHO cells revealed potential involvement of ASICIa in development, neurogenesis and axon guidance. In this proposal, we will focus on these discoveries and offer specific aims to define ASICIa-mediated signaling cascades in physiological conditions and in neurological disorders. Our group is highly experienced in using proteomics to identify novel cellular mechanisms in neuronal disorders and in using neurophysiology to characterize channel function.
Aim 1. Define the signaling pathways activated by ASICIa channels.
Aim 2. Determine the role of ASICIa channels in neuronal development.
Aim 3. Define distinct ASICIa-mediated signaling pathways in pathological conditions.
ASICIa is a novel target for stroke. The success of the proposed studies will dramatically advance our understanding ofthe functions as well as regulations of these important channels. Identifying ASICIa mediated pathways specific to pathological conditions will provide critical information for designing novel therapeutic interventions against neurological diseases with minima side effects.
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