The focus of this proposal is to determine the role of dystrophin-glycoprotein complex (DGC) in extracellular matrix remodeling and its impact on the three-dimensional myocardial fiber structure and ventricular wall motion. Using state-of-the-art MR technology (diffusion tensor MRI and cardiac tagging), we seek to characterize changes in myocardial fiber structure due to remodeling of the extracellular matrix in cardiomyopathic hearts with defects in DGC and associated proteins, and to elucidate the impact of such structural changes on regional myocardial contractility. Histologic and immunocytochemical methods will be employed to elucidate molecular/cellular changes that underlie the macroscopic structural changes and functional alterations. Four rodent models of dilated cardiomyopathy (DCM), the T0-2 DCM hamster (delta-sarcoglycan-deficient), the mdx mouse (dystrophin-deficient), the mdx/utm mouse (dystrophin/utrophin double knockout), and the dy/dy mouse (laminin alpha2-deficient), will be characterized on a 4.7T research scanner. Computational modeling will be employed to directly correlate functional abnormalities to changes in cardiac structure that occur at microscopic levels in elucidating the mechanisms that are responsible for myocardial dysfunction in DCM.
Our specific aims are: 1. To characterize functional and structural changes in cardiomyopathic Syrian hamster (T0-2) at distinct stages of the disease using both MRI and immunohistological methods; 2. To document longitudinal changes in myocardial structure and regional ventricular wall motion in mdx, mdx/utrn, and dy/dy mouse; 3. To use experimental data and computational models to predict myocardial wall stress and to determine passive and active material properties of normal and diseased hearts. This is a multi-disciplinary project that involves both technology development and investigation of a common cardiovascular disease with integrative approaches. Experimental and computational approaches will be applied to understand cellular mechanisms of pathophysiological processes that are responsible for their functional manifestations in vivo. Methods developed in this proposal will provide new means in elucidating the molecular mechanism of cardiac dysfunction not only in DCM but also in other cardiovascular diseases.
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