Molecular Dissection of Cardiac Conduction System Development

心脏传导系统开发的分子解剖

• 批准号: 7758182
• 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/7758182
• 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; 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; Screening procedure; 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; 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）：该提案描述了为从博士后研究员过渡到独立研究者而量身定制的基础研究培训计划。主要研究者已完成内科住院医师培训计划，旨在完成心脏病学临床进修培训。本文描述的提议将促进对心脏发育和疾病的转录调节的控制。在这方面，德克萨斯大学西南分校分子生物学系主席、该领域的世界权威埃里克·奥尔森博士将成为理想的导师。他过去培养了许多博士后研究员，并赞助了以前和现任的医学科学家。此外，还提议成立一个科学咨询委员会，该委员会不仅会定期对数据、假设和拟议的实验提出建设性批评，而且会就作为一名独立且富有成效的医师科学家的职业发展提供宝贵的建议。预计咨询委员会的成员将在提供他们的专业知识和独特的试剂以促进拟议的研究计划方面发挥无价的作用。该研究将重点阐明心脏传导系统发育和成熟的分子机制。 Willecke 和 Olson 实验室最近的工作证实，连接蛋白 30.2 (Cx30.2) 基因是发育中的房室和窦房结的一个有价值的标记。拟议的实验将以这一观察为基础，利用小鼠作为模型系统来研究人类发育和疾病，以增进我们对传导系统形式和功能的了解。具体目标包括以下内容：1) 定义正确传导系统发育所需的 Cx30.2 基因调控元件，2) 通过创建新型遗传工具和技术分离和操纵 Cx30.2+ 传导细胞，3) 分析 GATA4 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系将提供理想的跨学科环境，不仅可以进行拟议的实验，而且可以发展成为一名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，其失调会导致心律失常。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有一天可能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。