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.
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