Project Grant K08HL171874

WNT SIGNALING IN THE PATHOGENESIS OF ATRIAL FIBRILLATION - PROJECT SUMMARY / ABSTRACT ATRIAL FIBRILLATION (AF) IS A COMMON SUSTAINED CARDIAC ARRHYTHMIA WITH ASSOCIATED RISKS THAT INCLUDE STROKE, HEART FAILURE, AND DEATH. DESPITE THE PUBLIC HEALTH BURDEN, OUR UNDERSTANDING OF THE PATHOPHYSIOLOGIC BASIS OF AF REMAINS INCOMPLETE, AND THIS IS REFLECTED IN THE LACK OF THERAPEUTIC ADVANCEMENT. THIS PROPOSAL AIMS TO LEVERAGE THE CLINICAL AND SCIENTIFIC EXPERTISE THAT DR. BAPAT HAS DEVELOPED THUS FAR TO EXPLORE A NOVEL PATHWAY IN AF, ALL WHILE ALLOWING HIM TO GROW AS A SCIENTIST UNDER THE DIRECT MENTORSHIP AND GUIDANCE OF TWO VERY ACCOMPLISHED PHYSICIAN SCIENTISTS. DR. BAPAT HAS PRODUCED SUBSTANTIAL DATA WORKING WITH MOUSE MODELS OF AF. HE CONTRIBUTED TO A RECENT PUBLICATION THAT IDENTIFIED MURINE DEFICIENCY OF ZFHX3, A GENE IMPLICATED IN HUMAN AF, AS PATHOLOGIC, LEADING TO ATRIAL ARRHYTHMIA, FIBROSIS, AND CONTRACTILE DYSFUNCTION. IN ADDITION, HE HAS EXTENSIVELY STUDIED MOUSE MODELS OF "ACQUIRED" AF RESULTING FROM OBESITY OR SEPSIS. IN EXCITING PRELIMINARY DATA, NON-CANONICAL WNT SIGNALING HAS BEEN NOTED TO BE UPREGULATED IN BOTH GENRES OF AF PATHOGENESIS. AS THE DOWNSTREAM CONSEQUENCES INCLUDE EFFECTS ON CALCIUM HANDLING, STRESS SIGNALING, INFLAMMATION, AND FIBROSIS, THERE IS A FEASIBLE BIOLOGICAL LINK THAT WARRANTS FURTHER EXPLORATION. IN ADDITION, DR. BAPAT HAS DEMONSTRATED THE EFFICACY OF INHIBITING SERUM GLUCOCORTICOID KINASE 1 (SGK1), WHICH LIES DOWNSTREAM TO NON-CANONICAL WNT SIGNALING, IN MODELS OF OBESITY- RELATED AF. THIS PROPOSAL'S OVERARCHING OBJECTIVE IS TO BETTER DEFINE THE ROLE OF NON-CANONICAL WNT SIGNALING IN VARIOUS MODELS OF AF AND THEN DETERMINE WHETHER INTERVENING ON THIS SIGNALING PATHWAY MAY BE PROTECTIVE. FIRST, DR. BAPAT PROPOSES TO EXPAND UPON OUR EXISTING UNDERSTANDING OF ZFHX3-DEFICIENCY RELATED ATRIAL PATHOLOGY BY ADDRESSING ANY POSSIBLE CONFOUNDING RELATED TO DEVELOPMENTAL EFFECTS. HE HAS GENERATED MICE WITH INDUCIBLE, CARDIAC-RESTRICTED ZFHX3 DEFICIENCY, AND WILL STUDY THEIR CARDIAC PHENOTYPE, WITH A PARTICULAR INTEREST ON WNT SIGNALING AND AF PROPENSITY. HE THEN WILL STUDY A MODEL OF SEPSIS-RELATED AF, GENERATED BY PERFORMING CECAL LIGATION AND PUNCTURE (CLP). PRELIMINARY DATA REVEALS AN UPREGULATION IN WNT SIGNALING AND SGK1 ACTIVATION, AND HE WILL ATTEMPT TO RESCUE ARRHYTHMOGENESIS WITH GENETIC SGK1 INHIBITION. FINALLY, HE WILL UTILIZE A MULTI-OMIC ASSAY TO UNDERSTAND THE TRANSCRIPTIONAL EFFECTS OF CLP ON ATRIAL TISSUE THAT MAY BE DRIVING ARRHYTHMOGENESIS. THIS WORK WILL TAKE PLACE IN THE CARDIOVASCULAR RESEARCH CENTER AT THE MASSACHUSETTS GENERAL HOSPITAL (MGH) AND AT THE BROAD INSTITUTE OF MIT AND HARVARD UNDER THE MENTORSHIP OF DR. PATRICK ELLINOR, THE CHIEF OF CARDIOLOGY AT MGH, AND DR. SAUMYA DAS, AN ASSOCIATE PROFESSOR AT HARVARD MEDICAL SCHOOL. DR. BAPAT'S GOAL IS TO BECOME AN INDEPENDENT BASIC SCIENTIST WITH EXPERTISE IN THE MECHANISTIC BASIS FOR CARDIAC ARRHYTHMIAS. HE IS DEDICATED TO BECOMING AN INDEPENDENT INVESTIGATOR AND TO USE THE RESEARCH PERFORMED FOR THE K08 AS A SPRINGBOARD FOR AN R01 APPLICATION IN THE FUTURE.