The Role of Notch Signaling in Arrhythmogenesis

Notch 信号传导在心律失常发生中的作用

• 批准号: 8585205
• 负责人: STACEY Lynn RENTSCHLER
• 金额: $ 10.35万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-05 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8585205
• 关键词: Role; Notch; Signaling; Arrhythmogenesis

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.

描述（由申请人提供）： 项目摘要/摘要：该提案描述了一个为期五年的培训计划，用于发展心血管发育生物学的研究生涯。该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/博士学位。在分子生物学中。她目前在 Ruth L. Kirschstein 国家研究服务奖 (T32) 的支持下从事深入的基础科学研究，此外还获得医学部 Measey 基础科学奖学金奖的机构支持。拟议的研究将增强我们对先天性心脏病和心律失常的了解。它将在心脏发育领域公认的领导者、医学博士乔纳森·爱泼斯坦 (Jonathan Epstein) 的指导下进行。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医生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，可以培养一套技能，以便过渡到作为学术医师科学家的独立职业。参加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率。当心房和心室之间存在除房室结 -His 通路之外的电活动连接时，就会发生沃尔夫-帕金森-怀特 (WPW) 综合征，导致心室预激，并经常导致症状性心动过速或猝死作为首发临床表现。尽管最初的描述是在六十多年前，但人们对这些辅助电连接形成的致病机制知之甚少，部分原因是动物模型的缺乏。该候选人通过激活心肌细胞亚群中的 Notch 信号传导，开发了一种临床相关的 WPW 小鼠模型。 Notch信号传导是一种进化上保守的途径，与发育和疾病的许多方面有关，包括许多恶性肿瘤的发病机制，以及心脏发育缺陷，例如二叶式主动脉瓣和法洛四联症。然而，Notch 在心律失常表型中的作用此前尚未被描述。这种新模型的表征将同时提供对 WPW 发病机制的深入了解，并为研究潜在的治疗干预措施提供一个平台。该提案的目的是：1) 检验 Notch 信号传导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，2) 检验 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补知识方面的重大差距，最终可能转化为更先进的分子遗传学研究的可用性以及针对 WPW 患者改进的诊断和治疗选择。