Molecular Dissection of Cardiac Conduction System Development

描述(由申请人提供)：本方案描述了从博士后研究员到独立研究员过渡的量身定做的基础研究培训计划。首席研究员已经完成了内科的结构化住院医师培训计划，目的是完成心脏病学的临床团契培训。这里描述的建议将培养对心脏发育和疾病转录调控的掌握。在这方面，德克萨斯大学西南分校分子生物学教授、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，并资助了以前和现在的内科科学家。此外，还提出了一个科学咨询委员会，该委员会不仅将对数据、假设和拟议的实验提供定期的建设性批评，而且还将就作为一名独立和富有成效的内科科学家的职业发展提供宝贵的建议。还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宝贵的作用。这项研究将集中于阐明心脏传导系统发育和成熟的分子机制。Willecke和Olson实验室最近的工作证实，连接蛋白30.2(Cx30.2)基因是房室和窦房结发育的一个有价值的标记。拟议的实验将建立在这一观察的基础上，以促进我们对传导系统形式和功能的了解，使用小鼠作为研究人类发育和疾病的模型系统。具体目标包括：1)确定正确的传导系统发育所需的Cx30.2基因调控元件；2)通过创造新的遗传工具和技术来分离和操纵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设置，不仅可以进行拟议的实验，而且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，其失调导致心律失常的发生。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展有朝一日可能有助于阐明心律失常的病理生理学，并可能为新的抗心律失常药物的发现铺平道路。

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.