Molecular pathway to cardiac conduction defects

心脏传导缺陷的分子途径

• 批准号: 7006137
• 负责人: David Housman
• 金额: $ 45.93万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006137
• 关键词: congenital heart disorder; developmental genetics; enzyme activity; gene interaction; genetic mapping; genetic screening; genetically modified animals; heart block; heart conduction system; laboratory mouse; laboratory rabbit; molecular pathology; protein kinase; protein localization

The overall goal of Project IV (Housman) is to utilize the DMPK deficient mouse to analyze the genetic interactions that lead to cardiac conduction defects and heart block in this model system. The DMPK knockout mouse was developed to model characteristics of myotonic dystrophy, an inherited disorder in which cardiac conduction defects in the AV node and infra-Hisian and supra-Hisian tissue are a primary cause of premature death. The DMPK knockout mouse model strikingly resembles this pattern of cardiac conduct defect. Mice with absence of function for DMPK show normal cardiac conduction during the first two months of life. Between two and five months these animals develop lengthening of PR interval, lengthening of HIV interval and secondary and tertiary heart block. To define the molecular pathways that lead to this pathological outcome, we will carry out focused efforts to 1) determine the substrates for the protein kinase activity of DMPK 2) resolve the relative roles of two alternative splices splice forms of DMPK that show differential subcellular localization and 3) investigate the role of novel genes identified by transcriptional profiling, proteomic analysis and genetic modifier screens. We will develop a baseline for proteomic analysis of mouse cardiac development and pathology that will be applicable to other Projects in this program. We will also develop for executing mouse modifier gene mapping that will support the efforts of other Projects in this program in identifying gene interactions through genetic modifier mapping.

项目IV（Housman）的总体目标是利用DMPK缺乏的小鼠分析导致此模型系统中心脏传导缺陷和心脏阻滞的遗传相互作用。 DMPK敲除小鼠的开发是为了建模肌发育症的特征，这是一种遗传性疾病，其中AV节点中的心脏传导缺陷，Infra-Hisian和Supra-Hisian组织是过早死亡的主要原因。 DMPK敲除小鼠模型非常类似于这种心脏行为缺陷的模式。在生命的前两个月，缺乏DMPK功能的小鼠表现出正常的心脏传导。在两个到五个月之间，这些动物会延长PR间隔，HIV间隔以及继发性和第三纪心脏的延长。为了定义导致这种病理结果的分子途径，我们将进行重点努力1）确定DMPK的蛋白激酶活性的底物2）解决DMPK的两种替代剪接形式的相对作用，这些剪接形式表现出差异亚细胞定位的定位，并通过固定分析和固有分析的新型GENES的作用，并研究了属于蛋白质的新作用。我们将开发一个基准，用于对小鼠心脏发育和病理的蛋白质组学分析，该分析适用于该计划中的其他项目。我们还将开发用于执行鼠标修饰符基因映射，以支持该程序中其他项目通过遗传修饰符映射识别基因相互作用的工作。