Molecular pathway to cardiac conduction defects

Project IV （Housman）的总体目标是利用DMPK缺陷小鼠来分析该模型系统中导致心脏传导缺陷和心脏传导阻滞的遗传相互作用。DMPK基因敲除小鼠被用来模拟肌强直性营养不良的特征，肌强直性营养不良是一种遗传性疾病，在这种疾病中，房室结和hisian下组织和hisian上组织的心脏传导缺陷是导致过早死亡的主要原因。DMPK基因敲除小鼠模型与这种心脏传导缺陷的模式惊人地相似。缺乏DMPK功能的小鼠在出生后的头两个月心脏传导正常。在2至5个月之间，这些动物出现PR间期延长，HIV间期延长以及二级和三级心脏传导阻滞。为了确定导致这种病理结果的分子途径，我们将集中努力：1)确定DMPK蛋白激酶活性的底物；2)解决显示不同亚细胞定位的DMPK的两种可选剪接形式的相对作用；3)研究通过转录谱分析、蛋白质组学分析和遗传修饰筛选鉴定的新基因的作用。我们将为小鼠心脏发育和病理的蛋白质组学分析制定一个基线，这将适用于本计划的其他项目。我们还将开发用于执行小鼠修饰基因定位的方法，以支持本项目中通过基因修饰基因定位识别基因相互作用的其他项目的工作。

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.