The Role of Notch Signaling in Arrhythmogenesis

描述（由申请人提供）：项目概要/摘要：本提案描述了一个为期五年的心血管发育生物学研究职业发展培训计划。候选人是宾夕法尼亚大学的心脏病学研究员，拥有医学博士学位。博士在分子生物学中。她目前从事由Ruth L. Kirschstein国家研究服务奖（T32），并获得医学部Measey基础科学奖学金的机构支持。这项拟议的研究将提高我们对先天性心脏病和心律失常的认识。它将在乔纳森·爱泼斯坦医学博士的指导下进行。心脏发育领域公认的领导者。他是医学教授，宾夕法尼亚大学心血管研究所（CVI）的科学主任。他指导了许多博士后研究员和研究生。一个由才华横溢的临床科学家组成的咨询委员会已经成立，为职业发展和科学提供指导。宾夕法尼亚大学和CVI的环境提供了广泛的资源，合作，核心设施和知识专长。这是一个理想的培训环境，以发展一套技能，以过渡到一个独立的职业生涯作为一个学术医生-科学家。参与教学课程和教师专业发展研讨会将提高该计划的教育成功。预激综合征（WPW）是指房室结-希氏通路以外的电活动连接存在于心房和心室之间，导致心室预激，常以症状性心动过速或猝死为首发临床表现。尽管其最初的描述超过60年前，很少有人知道的病因机制的形成，这些附属电连接的部分原因是缺乏动物模型。该候选人通过激活心肌细胞亚群中的Notch信号转导，开发了临床相关的WPW小鼠模型。Notch信号传导是一种进化上保守的途径，其涉及发育和疾病的许多方面，包括许多恶性肿瘤的发病机制，以及心脏发育缺陷，如二叶主动脉瓣和法洛四联症。然而，Notch在白血病表型中的作用以前没有被描述过。这种新模型的表征将同时提供对WPW发病机制的洞察，并将为研究潜在的治疗干预提供平台。该提案的目的是：1）验证Notch信号通过细胞自主和非细胞自主机制调节旁路形成和心脏电生理特性的假设，以及2）验证Notch的组成性激活通过AV管心肌的异常模式导致WPW的假设。完成本提案中概述的研究将弥合知识上的重要差距，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.