Heart disease resulting from cardiac contractile dysfunction is the number one killer of people in the US today. The proteins that regulate cardiac contractile are under the tight post-translational modification (PTM) regulation of kinase phosphorylation and phosphatase de-phosphorylation. Central to the regulation of cardiac muscle contraction is the troponin (Tn) protein complex. In response to cardiac stress the Tn complex is subjected to a number of PTMs. Phosphorylation represents the primary mechanism of muscle PTM and it's tight balance is critical to normal heart function. Other non-phosphorylation Tn PTMs also occur. To date most Tn protein PTMs have been studied as isolated events, however the combined function of multiple Tn PTMs cannot be determined from function of the isolated events. This proposal investigates the primary troponin contractile regulation phosphorylation and other novel PTM events as combined events to better understand the physiological regulatory function of Tn PTMs as they occur in the heart. To this end, we will employ model troponin proteins and transgenic animal models containing single or multiple PTMs to evaluate biochemical and animal level function. The goal of these studies is to develop a more physiological understanding of the events that regulate heart function in order to identify novel drug targets to treat cardiac dysfunction.
A large number of people die every year from complications of cardiovascular disease related cardiac dysfunction. The relevance of this proposal to public health is to gain knowledge on the interaction of contractile regulatory proteins as a means to identify novel target molecules for drug development to improve cardiac function and limit the detrimental effects of cardiovascular disease.
|Davis, Jonathan P; Shettigar, Vikram; Tikunova, Svetlana B et al. (2016) Designing proteins to combat disease: Cardiac troponin C as an example. Arch Biochem Biophys 601:4-10|
|Li, Ning; Csepe, Thomas A; Hansen, Brian J et al. (2016) Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart. Circulation 134:486-98|
|Janssen, Paul M L; Biesiadecki, Brandon J; Ziolo, Mark T et al. (2016) The Need for Speed: Mice, Men, and Myocardial Kinetic Reserve. Circ Res 119:418-21|
|Biesiadecki, Brandon J (2016) Myofilament modulation of contraction. Arch Biochem Biophys 601:1-3|
|Brundage, Elizabeth A; Biesiadecki, Brandon J; Reiser, Peter J (2015) Nucleotide and protein sequences for dog masticatory tropomyosin identify a novel Tpm4 gene product. J Muscle Res Cell Motil 36:339-47|
|Roof, Steve R; Ho, Hsiang-Ting; Little, Sean C et al. (2015) Obligatory role of neuronal nitric oxide synthase in the heart's antioxidant adaptation with exercise. J Mol Cell Cardiol 81:54-61|
|Little, Sean C; Curran, Jerry; Makara, Michael A et al. (2015) Protein phosphatase 2A regulatory subunit B56Î± limits phosphatase activity in the heart. Sci Signal 8:ra72|
|Biesiadecki, Brandon J; Ziolo, Mark T (2015) Should we treat heart failure with phosphatase inhibitors? Better to start at the end. J Mol Cell Cardiol 89:116-8|
|Biesiadecki, Brandon J; Davis, Jonathan P; Ziolo, Mark T et al. (2014) Tri-modal regulation of cardiac muscle relaxation; intracellular calcium decline, thin filament deactivation, and cross-bridge cycling kinetics. Biophys Rev 6:273-289|
|Lou, Qing; Hansen, Brian J; Fedorenko, Olga et al. (2014) Upregulation of adenosine A1 receptors facilitates sinoatrial node dysfunction in chronic canine heart failure by exacerbating nodal conduction abnormalities revealed by novel dual-sided intramural optical mapping. Circulation 130:315-24|
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