Elucidation of the Development and Function of the Cardiac Conduction System

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PROJECT SUMMARY/ABSTRACT This five-year proposal will provide a platform for Dr. Goodyer’s successful transition to an independent physician scientist investigating novel mechanisms for the prevention and treatment of cardiac rhythm disorders. Specific mentorship and training opportunities have been tailored to build on the foundation of the applicant. Dr. Goodyer will be mentored by Dr. Sean M. Wu, Associate Professor of Medicine and Pediatrics and Dr. Anne Dubin, Professor of Pediatrics, Section Chief of Pediatric Electrophysiology (EP). Additionally, an outstanding advisory team of internationally-renowned scientists has been selected, each advisor with unique experiences and skillsets in fields ranging from basic science EP to translational medicine. Dr. Goodyer’s training plan lays out a personalized program for developing his proficiency in the following key areas: 1. Use of human induced pluripotent stem cells (hiPSCs) to functionally evaluate novel cardiac conduction system (CCS) genes; 2. Small animal phenotyping skills for in vivo analyses of CCS development and function; 3. Knowledge and techniques in basic science EP; and, 4. Professional development including leadership, grant writing and science communication skills. The training plan includes experiences from Stanford courses on stem cell research (eg. STEMREM 201B: Stem Cells and Human Development), weekly seminars on cardiology and translational medicine, renowned workshops on leadership and communication as well as a tailored externship focused on advanced basic science EP techniques in the lab of advisor Dr. Chiamvimonvat, Professor of Cardiovascular Medicine at University of California Davis. These mentorship and training activities are tailored to enable the candidate to achieve specific research goals aimed at the elucidation of CCS development and function. In Aim 1, Dr. Goodyer will investigate the role of a novel, intracellular, CCS-specific gene Cpne5 (copine 5), uncovered in his recently published work in Circulation Research and associated with human heart rate variation by independent genome wide association studies. The applicant will evaluate the function of Cpne5 in conduction cells by performing in vitro loss- and gain-of-function assays using both isolated mouse and hiPSC-derived CCS cells. In Aim 2, the candidate will further investigate Cpne5 in the context of CCS development and disease in vivo by comprehensive cardiac and electrophysiological phenotyping of CRISPR-Cas9 generated Cpne5 systemic knockout mice. Finally, Aim 3 capitalizes on the applicant’s recent discovery of another previously unknown CCS-specific marker. Specifically, by targeting this cell surface marker the applicant will validate the use of a novel antibody-based optical imaging method for visualizing the CCS in human hearts ex vivo. These studies will provide a proof-of-principle for the in vivo labeling of cardiac substructures and lay the foundation for translational opportunities in the real-time visualization of the CCS during cardiac interventions to prevent accidental intraoperative damage to the CCS.