The Mouse Production and Ventricular Function Core (Unit C) has two major aims as dictated by Projects 1-3: 1) production of mutant mouse models of familial hypertrophic cardiomyopathy (FHC) and dilated cardiomyopathy (DCM) and 2) characterization of the phenotypes of these animals using both in vivo and in vitro methods. Production of mice will be accomplished in the laboratory of our co-investigators Drs. Jeffrey Robbins and James Gulick (Univ. of Cincinnati) using overexpression of transgenes linked to a cardiac specific myosin heavy chain promoter. Our collaborators Drs. Jon Seidman (Harvard Medical School) and James Lessard (Univ. of Cincinati) will provide additional mice with both myosin and actin mutations. In vivo phenotypic characterization will take place in the laboratory of Dr. David Kass (Johns Hopkins School of Medicine) by use of a miniaturized conductance/micromanometer catheter system for simultaneous measurement of left ventricular (LV) pressure and volume under near physiologic conditions. These measurements allow estimation of a variety of sophisticated parameters of systolic and diastolic function that have been previously characterized in larger mammals, including man. In vitro phenotypic characterization will be accomplished in the laboratory of Dr. Martin LeWinter (University of Vermont), using a buffer-perfused, isovolumically contracting, isolated heart preparation. The latter preparation provides estimates of a number of functional parameters under less physiologic but more controlled experimental conditions than are possible in vivo. It also provides a mechanoenergetic analysis of the efficiency and economy of the contractile machinery by relating its mechanical output (pressure-volume area or force-time integral) to its chemical energy input (oxygen consumption). In vivo and in vitro LV chamber properties delineated in the Core will be used to better understand how specific mutations result in a FHC versus a DCM phenotype in two ways: 1) they will be correlated with muscle strip (myofilament) and myofibril properties determined in Project 3 as a component of systematic integration of the results of all of the Projects and the Core at increasing levels of system complexity; 2) by studying the temporal evolution of phenotypes in selected FHC and DCM models, we will determine which chamber properties are primary and which are secondary manifestations of specific mutations. The latter studies should lead to a better mechanistic understanding of the adaptations and maladaptations that occur in response to sarcomeric protein mutations.
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