The Role of Notch Signaling in Arrhythmogenesis

描述(由申请人提供)：项目摘要/摘要：本提案描述了一项为期五年的培训计划，旨在发展心血管发育生物学的研究生涯。这位候选人是宾夕法尼亚大学的心脏病学研究员，拥有分子生物学的医学博士学位。她目前从事由Ruth L.Kirschstein国家研究服务奖(T32)支持的密集基础科学研究，并获得医学部测量基础科学奖学金奖的机构支持。这项拟议的研究将增进我们对先天性心脏病和心律失常的了解。它将在乔纳森·爱泼斯坦的指导下进行，爱泼斯坦医学博士是心脏发展领域公认的领导者。他是医学教授，也是宾夕法尼亚大学心血管研究所(CVI)的科学主任。他曾指导过许多博士后研究员和研究生。一个由有才华的临床医生和科学家组成的咨询委员会已经成立，以提供职业发展和科学方面的指导。宾夕法尼亚大学和CVI的环境提供了广泛的资源、合作、核心设施和智力专长。这是一个理想的培训环境，可以培养一套技能，以便过渡到作为学术内科科学家的独立职业生涯。参加教学课程和教师专业发展研讨会将提高该项目的教育成功。沃尔夫-帕金森-怀特(Wolff-Parkinson-White，WPW)综合征是指房室结外的电活动连接--His通路存在于心房和脑室之间，导致室性预激，通常导致症状性心动过速或猝死为首发临床症状。尽管它最初的描述是在60多年前，但人们对这些附属电连接形成的原因知之甚少，部分原因是缺乏动物模型。这位候选人通过激活心肌细胞亚群中的Notch信号，开发了一种临床上相关的WPW小鼠模型。Notch信号通路是一条进化上保守的信号通路，与许多发育和疾病有关，包括许多恶性肿瘤的发病机制，以及心脏发育缺陷，如二尖瓣主动脉瓣和法洛四联症。然而，Notch在心律失常表型中的作用以前还没有被描述过。这一新模型的特征将同时为WPW的发病机制提供洞察力，并将为研究潜在的治疗干预措施提供一个平台。该建议的目的是：1)验证Notch信号通过细胞自主和非细胞自主机制调节旁道形成和心脏电生理特性的假说；2)验证Notch结构性激活通过房室管心肌异常构型导致WPW的假说。这项建议中概述的研究的完成将弥合知识上的一个重要差距，这一差距最终可能转化为更先进的分子遗传学研究的可用性，并改善WPW患者的诊断和治疗选择。

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT: This proposal describes a five-year training program for development of a research career in cardiovascular developmental biology. The candidate is a cardiology fellow at the University of Pennsylvania with an M.D./Ph.D. in molecular biology. She is currently engaged in intensive basic science research supported by the Ruth L. Kirschstein National Research Service Award (T32), and additionally receives institutional support from the Department of Medicine Measey Basic Science Fellowship Award. The proposed research will enhance our understanding of congenital heart disease and arrhythmias. It will be carried out under the mentorship of Jonathan Epstein, M.D. a recognized leader in the field of cardiac development. He is a professor of Medicine, and the scientific director of the University of Pennsylvania Cardiovascular Institute (CVI). He has mentored numerous postdoctoral fellows and graduate students. An advisory committee of talented clinician-scientists has been assembled to offer guidance in career development and science. The environment of Penn and the CVI provides extensive resources, collaborations, core facilities and intellectual expertise. This is an ideal training setting to develop a skill set in order to transition to an independent career as an academic physician- scientist. Participation in didactic courses and faculty professional development seminars will enhance the educational success of the program. Wolff-Parkinson-White (WPW) syndrome occurs when an electrically active connection apart from the AV node-His pathway exists between the atria and ventricles, resulting in ventricular pre-excitation and often leading to symptomatic tachycardias or sudden death as the first clinical manifestation. Despite its initial description over sixty years ago, little is known about the causative mechanisms underlying the formation of these accessory electrical connections due in part to a paucity of animal models. The candidate has developed a clinically relevant murine model of WPW through activation of Notch signaling in a subset of cardiomyocytes. Notch signaling is an evolutionarily conserved pathway that has been implicated in many aspects of development and disease, including the pathogenesis of many malignancies, as well as cardiac developmental defects such as bicuspid aortic valve and tetralogy of Fallot. However, a role for Notch in arrhythmic phenotypes has not previously been described. Characterization of this novel model will simultaneously provide insight into the pathogenesis of WPW and will provide a platform for studying potential therapeutic interventions. The aims of the proposal are: 1) To test the hypothesis that Notch signaling regulates formation of accessory pathways and cardiac electrophysiologic properties via both cell autonomous and non cell-autonomous mechanisms, and 2) To test the hypothesis that constitutive activation of Notch results in WPW through abnormal patterning of AV canal myocardium. Completion of the studies outlined in this proposal will bridge a vital gap in knowledge that may ultimately translate into the availability of more advanced molecular genetic studies and improved diagnostic and therapeutic options for WPW patients.