Molecular pathway to cardiac conduction defects

项目IV(Housman)的总体目标是利用DMPK缺陷小鼠在该模型系统中分析导致心脏传导缺陷和心脏传导阻滞的遗传交互作用。DMPK基因敲除小鼠是为了模拟强直性肌营养不良症的特征而发展起来的，强直性肌营养不良症是一种遗传性疾病，在这种疾病中，房室结和下丘脑和上丘脑组织中的心脏传导缺陷是过早死亡的主要原因。DMPK基因敲除小鼠模型与心脏传导缺陷的这种模式惊人地相似。DMPK功能缺失的小鼠在生命的头两个月表现出正常的心脏传导。在2-5个月内，这些动物出现PR间期延长、HIV间期延长以及二次和三次心脏传导阻滞。为了确定导致这种病理结果的分子途径，我们将集中开展以下工作：1)确定DMPK蛋白激酶活性的底物；2)解决DMPK两种不同剪接剪接形式的相对作用；3)通过转录图谱、蛋白质组分析和遗传修饰筛选，研究新基因的作用。我们将为小鼠心脏发育和病理的蛋白质组学分析开发一个基线，该基线将适用于该计划的其他项目。我们还将开发用于执行小鼠修饰基因作图的工具，这将支持该计划中其他项目通过遗传修饰作图识别基因交互作用的努力。

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.