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 expression in transgenic mice. Over-expression of wild type proteins for rescue studies (MLP), or expression of dominantly active proteins will be utilized. Alternatively, gene- targeting strategies (via homologous recombination in ES cells) are currently fully operative in our Program. The Chien lab has extensive experience in the generation, identification, breeding, and characterization of both transgenic and gene-targeted mouse models of cardiac physiology and disease. This Core Unit will provide services to assist in the design of the appropriate constructs, the testing of the constructs in cultured cell models, and the subsequent generation of 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 Cell Biology core. Accordingly, the objectives of the core unit are five-fold: 1) To design and test appropriate transgenes in in vitro systems; 2) To generate appropriate lines of transgenic and gene-targeted mice for various projects in the Program; 3) To identify founders and to breed/maintain appropriate lines of mice; 4) To knockout specific candidate regulatory genes via homologous recombination. 5) To breed and generate lines of mice required for cardiac restricted or conditional gene targeting via CRE-lox strategies.
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