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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/摘要这份为期五年的提案将为古德耶博士成功过渡到一个独立的公司提供一个平台。研究预防和治疗心律失常的新机制的医生科学家紊乱具体的指导和培训机会是根据申请人。Goodyer博士将由Sean M博士指导。吴，医学和儿科副教授和安妮·杜宾博士，儿科教授，儿科电生理学（EP）科科长。此外，由国际知名科学家组成的优秀顾问团队，每位顾问都具有独特的从基础科学EP到转化医学等领域的经验和技能。古德耶医生培训计划制定了一个个性化的计划，以发展他在以下关键领域的熟练程度：1。使用人诱导多能干细胞（hiPSCs）的功能评估新的心脏传导系统 (CCS)基因; 2.用于CCS发育和功能的体内分析的小动物表型分析技能; 3. 基础科学EP的知识和技术;以及，4。专业发展，包括领导力，补助金写作和科学沟通技巧。培训计划包括来自斯坦福大学课程的经验，干细胞研究（例如，STEMREM 201 B：干细胞和人类发展），每周研讨会，心脏病学和转化医学，著名的领导力和沟通研讨会，以及量身定制的实习生，专注于顾问Chiamvimonvat博士实验室的先进基础科学EP技术，加州戴维斯大学心血管医学教授。这些指导和培训活动量身定制，使候选人能够实现旨在阐明CCS的特定研究目标发展和功能。在目标1中，Goodyer博士将研究一种新的，细胞内的，CCS特异性的基因Cpne 5（copine 5），在他最近发表的《循环研究》和相关研究中发现，与人类心率变异的独立基因组关联研究。申请人将评估 Cpne 5在传导细胞中的功能，通过使用两种方法进行体外功能丧失和获得测定，分离的小鼠和hiPSC衍生的CCS细胞。在目标2中，候选人将进一步研究通过全面的心脏和电生理检查，了解CCS在体内的发展和疾病情况 CRISPR-Cas9产生的Cpne 5系统性敲除小鼠的表型分析。最后，Aim 3利用了申请人最近发现了另一种以前未知的CCS特异性标记。具体来说，通过瞄准这个细胞表面标记物申请人将验证基于抗体的新型光学成像方法的使用，在离体人类心脏中可视化CCS。这些研究将为体内免疫治疗提供原理证明。标记心脏亚结构并为实时平移机会奠定基础在心脏介入手术期间可视化CCS，以防止术中对CCS造成意外损坏。