Myofilament degeneration is an important pathological process in progressive cardiomyopathy leading to heart failure. The goal of this proposal is to create and study a transgenic mouse model for neonatal cardiac failure based on the hypothesis that overexpression of tropomodulin (a regulatory component of the thin filament complex) in vivo will result in the disorganization of the sarcomere and abnormal cardiac responses. The tropomodulin transgene will be specifically expressed in the heart using the myosin heavy chain promoter. Transgene expression levels will be determined and cross-breeding initiated to modulate cardiac tropomodulin expression levels. Changes in cardiac gene expression, intracellular organization, contractile function, and physiology will be characterized as the neonatal heart attempts to compensate for myofibril degeneration. Cellular compensatory mechanisms for myofibril degeneration in neonatal cardiac tissue could involve cardiomyocyte hypertrophy and/or proliferation. Several experimental approaches will be carried out: 1. to confirm myofilament degeneration using confocal microscopy and morphometric analysis; 2. to determine the mRNA and protein expression of the myofibril components; 3. to screen for expression of mRNAs associated with hypertrophic response; and 4. to assess cardiac performance and function. After determining the changes occurring in vivo, isolated cardiomyocytes from transgenic mice will be cultured in order to perform high resolution structural analysis and to attempt """"""""rescue"""""""" experiments to restore normal myofibril architecture.
|Sussman, M A; Welch, S; Gude, N et al. (1999) Pathogenesis of dilated cardiomyopathy: molecular, structural, and population analyses in tropomodulin-overexpressing transgenic mice. Am J Pathol 155:2101-13|