Cardiac muscle contraction is dependent upon a cooperative interaction between thick and thin sarcomeric proteins. Mutations in tropomyosin (TM), an essential thin filament protein, cause both skeletal and cardiac myopathies, including familial hypertrophic cardiomyopathy (FHC). We have deve oped novel mouse mode s whereby these mutations induce concentric or dilated cardiomyopathy. Our long-term objective is to understand how specific amino acid changes in TM disrupt sarcomere assembly and function, thereby triggering the enactment of a cardiac hypertrophic response.
The Specific Aims of this proposal are: (1) To address how TM mutations in non-troponin T binding regions lead to cardiac hypertrophy; the focus of Specific Aim 1 is to develop mouse models encoding genetically altered TM to enhance the understanding of the role TM plays in the sarcomere during both normal and pathological conditions. (2) To identify changes in gene expression that occur in response to sarcomeric induced cardiac hypertrophy.
Specific Aim 2 will identify new and current genes that are transcriptionally activated/repressed following sarcomeric impairment and the onset of the cardiomypathic response. (3) To identify the chromosomal regions containing modifier genes associated with FHC a-TM180 hypertrophic cardiomyopathy. Using genetically inbred transgenic mouse lines which demonstrate marked differences in cardiac hypertrophy, the focus of Specific Aim 3 is to identify the chromosomal regions containing the gene(s) that modulate development of cardiac hypertrophy. Our research focuses on the importance of TM during mechanical and biochemical activity of normal and diseased cardiac muscle. We employ murine models that provide invaluable information on in vivo function of TM in the intact sarcomere. Our comprehensive approach will extend the understanding of the molecular mechanisms that are involved in the development and prevention of cardiac hypertrophy following mutations in the TM sarcomeric thin filament protein.
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