Several of the projects in the Program will utilize a combination of transgenic and gene-targeted mice to study the signaling mechanisms which lead to cardiac hypertrophy and/or dilated cardiomyopathy. In certain cases, transgenic approaches will be used to identify the role of a candidate signaling molecule in the activation of distinct molecular, morphological, or physiological features of hypertrophy. Cardiac-specific expression will be achieved via well-defined promoters that can drive cardiac-restricted fashion in transgenic mice. Alternatively, gene-targeted mice will generated to examine consequences of loss of function. In addition, certain projects will employ cardiac restricted gene targeting and/or cardiac restricted conditional gene targeting and transgene expression Standard transgenesis and gene-targeting strategies (via homologues recombination in ES cells) will be utilized. The Chen and Chien labs have extensive experience in the generation, identification, breeding, and characterization of both transgenic and gene targeted mouse models of cardiac physiology and disease. Core Unit B will provide services to assist in the design of the appropriate constructs, the testing of the constructs in cultured cell models, and subsequently generate gene-targeted and transgenic mice which harbor transgenes of interest. Finally, the founder mice will be identified, bred, and maintained in a core animal facility. In certain cases, the transgenic lines will be utilized for cultured myocardial cells which will be prepared in conjunction with the myocardial cell biology core. Accordingly, the objectives of the Core Unit are seven-fold: A) To design and test appropriate transgenes in vitro systems. B) To generate appropriate lines of transgenic and gene-targeted mice for various projects in the Program; C) To identify founders and to breed/maintain appropriate lines of mice; D) To knockout specific candidate regulatory genes via homologous recombination. E) To generate and breed lines of mice required for regionally gene targeting and over-expression via CRE-lox strategies. F) To generate and breed lines of mice required for cardiac-restricted conditional gene targeted and over-expression via CRE-lox strategies. G) To generate lines of mice containing specific amino acid changes within targeted genes.
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