Striated muscle contraction is dependent upon a cooperative interaction between thick and thin filament sarcomeric proteins. Tropomyosin (TM) plays an essential regulatory role in the sarcomere through its binding to actin and the troponin T (TnT) complex. Our long-term objective is to understand the importance of striated muscle TM isoforms and their post translational modifications in the myofilaments'response to mechanical and biochemical activity in normal and diseased cardiac muscle. This is important for biomedical research since mutations in TM cause hypertrophic and dilated cardiomyopathies that can lead to heart failure. Recent studies in our laboratory demonstrate that TnT binding domains in TM play a significant role in modifying sarcomeric performance. In this proposal, we will extend this work through an examination of the troponin binding domains of the b- and g-TM molecules, coupled with an examination of other regions within TM that modify thin filament function using both in vivo and in vitro approaches. To complement our TM structure-function analyses, we will also develop mouse models to determine the functional importance of TM phosphorylation in the heart.
The Specific Aims of this project are: c. 1. To ascertain the in vivo functional significance of TM isoform-specific amino acids in sarcomeric performance. We hypothesize that substitution of native a-TM for b-TM amino acids will decrease rates of contraction and relaxation, whereas g-TM substitution will increase these rates of cardiac performance. 2. To assess the in vitro functional significance of TM isoform specific amino acids. We will use in vitro biochemical studies to determine how a-, b-, and g-TM isoform-specific amino acid sequences affect binding to actin + troponin, influence actomyosin MgATPase activity, and affect the myosin S1-induced binding of TM to actin. 3. To determine the functional significance of TM phosphorylation. The focus of this aim is to test the hypothesis that genetically-designed mutations in TM that mimic phosphorylation or inhibit this process affect cardiac development and sarcomeric function. These experiments will be conducted using transgenic mice and thus provide unique in vivo models for addressing this significant research area.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-C (03))
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Przywara, Dennis
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University of Cincinnati
Schools of Medicine
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Holmes, Michael V; Exeter, Holly J; Folkersen, Lasse et al. (2014) Novel genetic approach to investigate the role of plasma secretory phospholipase A2 (sPLA2)-V isoenzyme in coronary heart disease: modified Mendelian randomization analysis using PLA2G5 expression levels. Circ Cardiovasc Genet 7:144-50
Simon, Jillian N; Chowdhury, Shamim A K; Warren, Chad M et al. (2014) Ceramide-mediated depression in cardiomyocyte contractility through PKC activation and modulation of myofilament protein phosphorylation. Basic Res Cardiol 109:445
Alves, Marco L; Dias, Fernando A L; Gaffin, Robert D et al. (2014) Desensitization of myofilaments to Ca2+ as a therapeutic target for hypertrophic cardiomyopathy with mutations in thin filament proteins. Circ Cardiovasc Genet 7:132-143
Rajan, Sudarsan; Pena, James R; Jegga, Anil G et al. (2013) Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout. Physiol Genomics 45:764-73
Mamidi, Ranganath; Mallampalli, Sri Lakshmi; Wieczorek, David F et al. (2013) Identification of two new regions in the N-terminus of cardiac troponin T that have divergent effects on cardiac contractile function. J Physiol 591:1217-34
Schulz, Emily M; Wieczorek, David F (2013) Tropomyosin de-phosphorylation in the heart: what are the consequences? J Muscle Res Cell Motil 34:239-46
Yar, Sumeyye; Chowdhury, Shamim A K; Davis 3rd, Robert T et al. (2013) Conserved Asp-137 is important for both structure and regulatory functions of cardiac ?-tropomyosin (?-TM) in a novel transgenic mouse model expressing ?-TM-D137L. J Biol Chem 288:16235-46
Schulz, Emily M; Wilder, Tanganyika; Chowdhury, Shamim A K et al. (2013) Decreasing tropomyosin phosphorylation rescues tropomyosin-induced familial hypertrophic cardiomyopathy. J Biol Chem 288:28925-35
Schulz, Emily M; Correll, Richard N; Sheikh, Hajer N et al. (2012) Tropomyosin dephosphorylation results in compensated cardiac hypertrophy. J Biol Chem 287:44478-89
Al Moamen, Nabeel J; Prasad, Vikram; Bodi, Ilona et al. (2011) Loss of the AE3 anion exchanger in a hypertrophic cardiomyopathy model causes rapid decompensation and heart failure. J Mol Cell Cardiol 50:137-46

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