Project Grant R03NS136719

ELUCIDATING THE ROLE OF KCNN1 IN RECOVERY FROM SPINAL CORD INJURY - ABSTRACT POTASSIUM CHANNEL PROTEINS ARE INVOLVED IN MANY ASPECTS OF HUMAN PHYSIOLOGY. SMALL CONDUCTANCE CALCIUM-ACTIVATED POTASSIUM CHANNELS (SK CHANNELS) ARE VOLTAGE-INDEPENDENT AND WIDELY EXPRESSED IN EXCITABLE CELLS. OUR LABORATORY DETERMINED THAT EXPRESSION OF KCNN1, WHICH ENCODES THE SK1 CHANNEL, IS UPREGULATED AFTER SPINAL CORD INJURY IN ZEBRAFISH. OUR PRELIMINARY DATA USING A POTASSIUM CHANNEL INHIBITOR, 4-AMINOPYRIDINE, DEMONSTRATES THAT INHIBITION ENHANCES SWIM RECOVERY IN ZEBRAFISH SUGGESTING MODULATION OF SK CHANNELS MAY BE POTENTIALLY USEFUL AS A THERAPEUTIC APPROACH FOR SCI. THE BROAD, LONG-TERM OBJECTIVE OF THE PROJECT IS TO DETERMINE THE ROLE OF SK1 IN RECOVERY FROM SPINAL CORD INJURY (SCI). TO ACHIEVE THIS GOAL, WE WILL FIRST CONSTRUCT KNOCKOUT AND TRANSGENIC ZEBRAFISH FOR BOTH PARALOGS OF THE SK1 CHANNEL. WE WILL DETERMINE WHETHER THESE LINES PROPERLY DEVELOP A SPINAL CORD AND USE OPTOGENETIC TECHNIQUES TO SPATIOTEMPORALLY CONTROL KCNN1 EXPRESSION AFTER SCI. SECOND, WE WILL USE PHARMACOLOGICAL APPROACHES TO DETERMINE HOW MODULATION OF SK CHANNELS MEDIATES FUNCTIONAL RECOVERY AFTER SCI. THESE STUDIES WILL CLARIFY THE ROLE OF SK CHANNELS AND SPECIFICALLY SK1 IN RECOVERY FROM SCI. WE EXPECT THAT THE DEVELOPED LINES WILL BE USEFUL TO STUDY ADDITIONAL NEUROLOGICAL PATHOLOGIES AND FACILITATE DRUG SCREENING TO IDENTIFY NEW THERAPEUTICS FOR NEURODEGENERATIVE DISEASES.