Project Grant F30HL184779

TRPM4 CHANNELS AND CARDIAC CONDUCTION DISEASE - PROJECT SUMMARY CARDIOVASCULAR DISEASE (CVD) IS A MAJOR CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE. ARRHYTHMOGENIC CARDIOVASCULAR DISEASE, INCLUDING SYNDROMES INVOLVING THE SPECIALIZED VENTRICULAR CONDUCTION SYSTEM (VCS), ACCOUNT FOR A SIGNIFICANT PROPORTION OF THE OVERALL CVD DISEASE BURDEN AND ESPECIALLY THOSE THAT PRESENT WITH SUDDEN CARDIAC DEATH. CURRENT THERAPEUTIC EFFORTS TO REDUCE THESE CONSEQUENCES OF ARRHYTHMOGENIC HEART DISEASE HAVE RELIED LARGELY ON DEVICE-BASED MODALITIES; THIS RELIANCE HIGHLIGHTS MAJOR GAPS IN KNOWLEDGE REGARDING THE UNDERLYING MECHANISTIC BASIS RESPONSIBLE FOR CONDUCTION SYSTEM DISEASE, AND UNDERSCORES HOW THESE GAPS IN KNOWLEDGE IMPEDE THE DEVELOPMENT OF TARGETED THERAPEUTICS. THE TRANSIENT RECEPTOR POTENTIAL MELASTATIN (TRPM) CHANNELS COMPRISE A FAMILY OF ION CHANNELS THAT PLAY KEY ROLES IN A REMARKABLY DIVERSE SET OF BIOLOGICAL PROCESSES, INCLUDING CELLULAR SENSING OF PAIN, TEMPERATURE AND TASTE. TRPM4 IS A NON-SELECTIVE CATION CHANNEL THAT HAS BEEN IMPLICATED IN SEVERAL FACETS OF CARDIOVASCULAR PHYSIOLOGY, MOST PROMINENTLY IN THE REGULATION OF CARDIAC RHYTHMICITY. A GROWING NUMBER OF LIKELY PATHOGENIC MUTATIONS IN TRPM4 HAVE BEEN REPORTED IN PATIENTS WITH PROGRESSIVE FAMILIAL HEART BLOCK TYPE I (PFHB1), ATRIOVENTRICULAR BLOCK, AND BRADYCARDIA. A RANGE OF EXPERIMENTAL STRATEGIES, INCLUDING FUNCTIONAL RECORDINGS OF IONIC CURRENTS IN HETEROLOGOUS EXPRESSION SYSTEMS, COMPUTATIONAL SIMULATIONS OF IMPULSE PROPAGATION IN CARDIOMYOCYTE STRANDS, AND GENE KNOCKOUT STUDIES IN MURINE MODELS, HAVE PROVIDED SOME INSIGHT INTO THE ROLE OF TRPM4 IN NORMAL PHYSIOLOGY AND DISEASE PATHOGENESIS, YET IMPORTANT GAPS IN KNOWLEDGE REMAIN. THE OBJECTIVE OF THIS PROPOSAL IS THUS TO UNDERSTAND THE MECHANISTIC BASIS FOR CARDIAC RHYTHM ABNORMALITIES ASCRIBED TO MUTATIONS IN TRPM4. USING A MULTI-DISCIPLINARY APPROACH INCLUDING HETEROLOGOUS EXPRESSION IN NON-EXCITABLE AND EXCITABLE CELLS, BIOCHEMICAL ASSAYS, COMPUTATIONAL MODELING AND NOVEL GENETICALLY ENGINEERED MURINE MODELS, I WILL ADDRESS THIS GAP IN KNOWLEDGE, FOCUSING ESPECIALLY ON THE ROLE OF TRPM4 IN NORMAL AND ABNORMAL CARDIAC ELECTROPHYSIOLOGY AND DISEASE PATHOGENESIS. MOREOVER, AS A BRIDGE TO THERAPEUTIC TRANSLATION, I ALSO EXPLORE THE EFFICACY OF POTENTIAL MECHANISM-BASED THERAPEUTICS IN A MURINE MODEL OF PFHB1. TAKEN TOGETHER, THESE EXPERIMENTS WILL PROVIDE NOVEL INSIGHTS INTO CONDUCTION SYSTEM PHYSIOLOGY IN HEALTH AND DISEASE AND MOVE US A STEP CLOSER TO REPURPOSING EXISTING FDA-APPROVED DRUGS FOR TREATMENT OF PATIENTS WITH TRPM4 AND RELATED CHANNELOPATHIES.