Molecular Dissection of Cardiac Conduction System Development

心脏传导系统开发的分子解剖

• 批准号: 8486477
• 负责人: NIKHIL Vilas MUNSHI
• 金额: $ 13万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8486477
• 关键词: Address; Advisory Committees; Algorithms; Alleles; Anti-Arrhythmia Agents; Arrhythmia; Automobile Driving; Basic Science; Binding Sites; Biological Assay; Biological Models; Cardiac; Cardiac conduction system; Cardiology; Cells; Clinical; Connexins; Coupled; Data; Development; Disease; Dissection; Electrocardiogram; Elements; Embryo; Enhancers; Fellowship; Fostering; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Enhancer Element; Genetic Markers; Genomics; Heart; Heterogeneity; Human Development; Instruction; Internal Medicine; Investigation; Knockout Mice; Knowledge; Laboratories; LacZ Genes; Light; Maps; Mentors; Methodology; Molecular; Molecular Biology; Mus; Mutation; Myocardium; Phenotype; Physicians; Play; Population; Postdoctoral Fellow; Principal Investigator; Property; RNA; Reagent; Regulatory Element; Research; Research Personnel; Research Training; Residencies; Role; Scientist; Sinoatrial Node; Sorting - Cell Movement; Structure; System; Systems Development; Techniques; Texas; Tissues; Training; Training Programs; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; Universities; Work; atrioventricular node; authority; base; career development; cell type; drug discovery; human disease; improved; in vivo; insight; loss of function; member; novel; programs; recombinase; regional difference; research study; screening; tool; transcription factor

DESCRIPTION (provided by applicant): This proposal describes a tailored basic research training program for the transition from post-doctoral fellow to independent investigator. The principal investigator has completed a structured residency training program in Internal Medicine with the intent to complete clinical fellowship training in Cardiology. The proposal described herein will foster a command of transcriptional regulation of cardiac development and disease. In this regard, Dr. Eric Olson, the chariman of Molecular Biology at the University of Texas at Southwestern and a world's authority in the field, will serve as the ideal mentor. He has trained numerous post-doctoral fellows in the past and has sponsored previous and current physician-scientists. Furthermore, a scientific advisory committee has been proposed that will not only provide regular constructive criticism of data, hypotheses, and proposed experiments but invaluable advice regarding career development as an independent and productive physician-scientist. It is also expected that members of the advisory committee will be invaluable in offering their expertise and unique reagents to foster the proposed research plan. The research will focus on elucidating the molecular mechanisms underlying development and maturation of the cardiac conduction system. Recent work in the Willecke and Olson laboratories has established that the connexin 30.2 (Cx30.2) gene is a valuable marker for the developing atrioventricular and sinoatrial nodes. The proposed experiments will build on this observation to advance our knowledge about conduction system form and function using the mouse as a model system to study human development and disease. The specific aims include the following: 1) Define the Cx30.2 gene regulatory elements required for proper conduction system development, 2) Isolate and manipulate Cx30.2+ conduction cells by creating novel genetic tools and techniques, and 3) Analyze the cell autonomous role of GATA4 in cardiac conduction system development. The Molecular Biology and Cardiology departments will provide the ideal interdisciplinary setting not only to conduct the proposed experiments but to develop as an independent clinician-scientist. RELEVANCE (See instructions): The cardiac conduction system coordinates the heart's normal rhythm, and its dysregulation contributes to arrhythmogenesis. Given that embryonic gene expression programs are often re-deployed during disease states, understanding development of the cardiac conduction system may someday shed light on arrhythmia pathophysiology and possibly pave the way for novel anti-arrhythmic drug discovery.

描述（由申请人提供）：本提案描述了一个量身定制的基础研究培训计划，用于从博士后研究员到独立研究员的过渡。主要研究者已完成内科住院医师结构化培训计划，旨在完成心脏病学临床研究员培训。本文所述的建议将促进心脏发育和疾病的转录调控的命令。在这方面，埃里克·奥尔森博士，分子生物学在得克萨斯大学西南和该领域的世界权威的主持人，将作为理想的导师。他在过去培养了许多博士后研究员，并赞助了以前和现在的医生科学家。此外，一个科学咨询委员会已经提出，不仅将提供定期的数据，假设和拟议的实验建设性的批评，但宝贵的意见，职业发展作为一个独立的和富有成效的医生科学家。我们还希望咨询委员会的成员能够提供宝贵的专业知识和独特的试剂，以促进拟议的研究计划。该研究将侧重于阐明心脏传导系统发育和成熟的分子机制。Willecke和Olson实验室最近的工作已经确定连接蛋白30.2（Cx30.2）基因是房室结和窦房结发育的有价值的标志物。拟议的实验将建立在这一观察的基础上，以小鼠作为研究人类发育和疾病的模型系统，推进我们对传导系统形式和功能的认识。具体目标包括：1）定义适当传导系统发育所需的Cx30.2基因调控元件，2）通过创建新的遗传工具和技术分离和操纵Cx30.2+传导细胞，3）分析GATA 4在心脏传导系统发育中的细胞自主作用。分子生物学和心脏病学部门将提供理想的跨学科环境，不仅可以进行拟议的实验，还可以发展为独立的临床医生科学家。相关性（参见说明）：心脏传导系统协调心脏的正常节律，其失调有助于心脏病的发生。鉴于胚胎基因表达程序经常在疾病状态下重新部署，了解心脏传导系统的发育可能有一天会揭示心律失常的病理生理学，并可能为新型抗心律失常药物的发现铺平道路。