Project Grant R21CA285254

HIGH-THROUGHPUT ASSESSMENT OF CHEMOTHERAPY-INDUCED CARDIOTOXICITY IN 3D HUMAN CARDIOMYOCYTES - HIGH-THROUGHPUT ASSESSMENT OF CHEMOTHERAPY-INDUCED CARDIOTOXICITY IN HUMAN CARDIOSPHERES PROJECT SUMMARY CHEMOTHERAPEUTIC AGENTS INCLUDING BOTH TRADITIONAL DRUGS (E.G., ANTHRACYCLINES) AND NEWER ONES (E.G., PROTEASOME INHIBITORS) ARE ASSOCIATED WITH CARDIAC ADVERSE EVENTS INCLUDING INCREASED RISK OF ARRHYTHMIAS. TREATMENT FOR ARRHYTHMIAS IS DIFFICULT WITH CURRENTLY AVAILABLE ANTIARRHYTHMIC DRUGS. DEVELOPMENT OF EFFECTIVE THERAPIES IS THEREFORE HIGHLY DESIRABLE AND CAN BE FACILITATED BY HUMAN CELL MODELS AND HIGH-THROUGHPUT ASSAYS. CARDIOMYOCYTES DERIVED FROM HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSC-CMS) HAVE PROVIDED A NEW PLATFORM FOR THE STUDIES OF DRUG-INDUCED SIDE EFFECTS AND DISEASE MODELING. HIPSC-CMS HAVE TRANSLATIONAL POTENTIAL TO IMPROVE CURRENT MODELS BY PROVIDING CLINICALLY RELEVANT CHARACTERISTICS REGARDING DISEASE PHENOTYPES AND RESPONSES TO DRUG TREATMENT. THEY CAN ALSO OVERCOME THE DIFFERENCES BETWEEN HUMAN AND ANIMAL CARDIAC PHYSIOLOGY AND CHALLENGES IN LONG-TERM MAINTENANCE OF PRIMARY HUMAN CARDIOMYOCYTES. CA2+ HANDLING ABNORMALITIES PLAY A CENTRAL ROLE IN THE PATHOPHYSIOLOGY OF HEART FAILURE AND ARRHYTHMIAS AND COULD BE PROMISING TARGETS FOR NOVEL THERAPEUTICS TO TREAT CHEMOTHERAPY-INDUCED CARDIOTOXICITY, SINCE CHEMOTHERAPY CAN CAUSE CA2+ TO BE RELEASED SPONTANEOUSLY AT THE WRONG TIMES DURING THE HEARTBEAT, THUS INDUCING ARRHYTHMIAS. OUR OBJECTIVE IS TO ACHIEVE AN ACCURATE AND HIGH-THROUGHPUT CA2+ TRANSIENT RECODING AND ANALYSES FOR FUNCTIONAL ASSESSMENT OF 3D HIPSC-CMS (CARDIOSPHERES). WE EXPECT THAT THIS TECHNOLOGY WILL ALLOW US TO DETECT CHEMOTHERAPY-INDUCED CARDIOTOXICITY AND EVALUATE POTENTIAL THERAPIES IN A HIGHLY EFFICIENT MANNER. OUR PROPOSED STUDY IS AN IMPORTANT COMPONENT FOR THE APPLICATION OF HIPSC-CMS IN THE STUDY OF CHEMOTHERAPY-INDUCED CARDIOTOXICITY. USING OUR STATE-OF-THE-ART EQUIPMENT AND COMPUTATIONAL TOOLS, WE AIM TO (1) ESTABLISH HIGH-THROUGHPUT FUNCTIONAL ASSESSMENT OF HUMAN CARDIOSPHERES FOR THE DETECTION OF CHEMOTHERAPY-INDUCED CARDIOTOXICITY, AND (2) EVALUATE NOVEL ANTIARRHYTHMIC THERAPIES TO MITIGATE CHEMOTHERAPY-INDUCED CARDIOTOXICITY. THE HUMAN CARDIOSPHERES WILL PROVIDE A BETTER MODEL FOR CHEMOTHERAPY-INDUCED ARRHYTHMIAS, SINCE CLINICAL ARRHYTHMIAS RESULT FROM THE COLLECTIVE BEHAVIOR OF CARDIOMYOCYTES WITHIN CARDIAC TISSUES. WE EXPECT THAT OUR HIGH THROUGHPUT FUNCTIONAL ASSAY WILL FACILITATE THE DISCOVERY OF NOVEL THERAPEUTIC TARGETS.