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Elucidation of the Development and Function of the Cardiac Conduction System

阐明心脏传导系统的发育和功能

基本信息

批准号：
10473531
负责人：
William R Goodyer
金额：
$ 16.65万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10473531
关键词：
Adult Advisory Committees Alleles Animals Antibodies Area Arrhythmia Backcrossings Basic Science Biological Biological Assay Biological Pacemakers Blood Circulation CRISPR/Cas technology Calcium California Cardiac Cardiac Myocytes Cardiac Output Cardiac Surgery procedures Cardiac conduction system Cardiac development Cardiology Cardiovascular system Categories Cell Count Cell Surface Proteins Cell physiology Cell surface Cells Childhood Clinical Communication Development Disease Dose Dyes Echocardiography Educational workshop Electrocardiogram Electrophysiology (science)Exercise Fluorescent Antibody Technique Foundations Gene Expression Gene Expression Profiling Generations Genes Goals Grant Harvest Heart Heart Rate Heterogeneity Human Human Development Image Immunofluorescence Immunologic In Vitro International Intervention Ion Channel Knock-out Knockout Mice Knowledge Label Leadership Life Link Measures Medicine Membrane Mentors Mentorship Methods Microscopy Molecular Molecular Analysis Monitor Mus Operative Surgical Procedures Pediatrics Phenotype Physicians Postdoctoral Fellow Prevention Protocols documentation Publishing Reporter Research Resolution Role Safety Science Scientist Signal Transduction Small Interfering RNA Stem Cell Research Structure System Systems Development Techniques Time Tissue-Specific Gene Expression Tissues Training Training Activity Transgenic Organisms Universities Variant Visualization Work Writing base career cell type copine diagnostic tool experience experimental study externship gain of function genome wide association study heart cell heart function heart rate variability heart rhythm heart visualization iatrogenic injury imaging modality in vivo induced pluripotent stem cell knock-down mid-career faculty near infrared dye new therapeutic target nodal myocyte novel novel diagnostics optical imaging overexpression prevent professor programs protein transport single-cell RNA sequencing skills stem cells targeted agent trafficking training opportunity translational medicine transmission process voltage

项目摘要

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.

项目总结/文摘