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：该提案描述了一项为期五年的心血管发育生物学研究职业的培训计划。候选人是宾夕法尼亚大学的心脏病学研究员，并拥有医学博士/ph.d。在分子生物学中。她目前正在接受露丝·柯希斯坦国家研究服务奖（T32）的支持，并获得了强化基础科学研究，并获得了医学系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不齐的理解。它将在乔纳森·爱泼斯坦（Jonathan Epstein）的指导下进行，医学博士是心脏发展领域公认的领导者。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。有才华的临床医生科学家的咨询委员会已经组装，以在职业发展和科学方面提供指导。宾夕法尼亚州和CVI的环境提供了广泛的资源，合作，核心设施和智力专业知识。这是一个理想的培训环境，可以开发技能，以便过渡到一个学术医师 - 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增强该计划的教育成功。 Wolff-Parkinson-White（WPW）综合征发生在主动性和心室之间存在的电活动连接外，导致心室前兴奋，并且通常导致有症状的心动过速或猝死作为第一次临床表现。尽管有60年前的最初描述，但对这些辅助电气连接形成的原因很少，部分原因是动物模型的缺乏。候选人通过在心肌细胞的一部分中激活Notch信号传导开发了与WPW相关的鼠模型。 Notch信号传导是一种进化保守的途径，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理，以及心脏发育缺陷，例如双质主动脉瓣和法洛的四边形。然而，先前尚未描述Notch在心律不齐表型中的作用。这种新型模型的表征将同时洞悉WPW的发病机理，并将为研究潜在的治疗干预措施提供平台。该提案的目的是：1）检验以下假设：Notch信号传导通过细胞自主和非细胞自主机制调节辅助途径和心脏电生理特性的形成，以及2）测试假设，以测试通过AV Canal myoccard的异常模式的Notch结果的组成型notch结果的组成型活化。该提案中概述的研究的完成将弥合知识的重要差距，这些差距可能最终转化为更先进的分子遗传研究，并改善WPW患者的诊断和治疗选择。