Signaling in pathological &physiological hypertrophy

University Of Colorado At Boulder, Boulder CO

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Abstract

DESCRIPTION: (provided by applicant): In response to a wide variety of stimuli, the heart has the ability to undergo hypertrophic growth. Hypertrophy can be a physiologic adaptive process during development or in response to exercise. It is initially adaptive after a pathological stimulus such as pressure overload but can become maladaptive and is, in fact, a leading predictor of congestive heart failure. The regulatory feedback systems leading to hypertrophy include a variety of intracellular factors and signaling cascades. Because the multiple factors and signaling pathways activated under these conditions are common to both stimuli, it is critical to understand which common and distinct pathways lead to pathologic versus physiological hypertrophy. We will use several transgenic models to help delineate the signaling processes involved in the progression of pathologic and physiologic hypertrophy. The cardiac phenotype of a transgenic line lacking an intracellular messenger (MEKKI) of a hypertrophic signaling cascade will be characterized for its response to pathologic and physiologic hypertrophic stimuli. In addition, this mouse will be crossed to three, well-characterized transgenic models for hypertrophic cardiomyopathy (HCM), which harbor specific mutations in cardiac sarcomeric proteins. One of these transgenic models has a mutation in the actin-binding domain of the murine a-myosin heavy chain (a-MHC) and is characterized by a gender specific increased ventricular mass. Additional models contain a missense mutation of cardiac troponin T (cTnT) or a truncated cTnT. Interestingly, cTnT mutations result in significantly decreased ventricular mass. These crossed animals will be analyzed to determine the integration and contribution of the MEKK1 intracellular pathway to the varied Phenotypes of HCM.