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.
|Nixon, Benjamin R; Walton, Shane D; Zhang, Bo et al. (2014) Combined troponin I Ser-150 and Ser-23/24 phosphorylation sustains thin filament Ca(2+) sensitivity and accelerates deactivation in an acidic environment. J Mol Cell Cardiol 72:177-85|
|Ho, Hsiang-Ting; Liu, Bin; Snyder, Jedidiah S et al. (2014) Ryanodine receptor phosphorylation by oxidized CaMKII contributes to the cardiotoxic effects of cardiac glycosides. Cardiovasc Res 101:165-74|
|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|
|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 7:132-43|
|Liu, Bin; Lopez, Joseph J; Biesiadecki, Brandon J et al. (2014) Protein kinase C phosphomimetics alter thin filament Ca2+ binding properties. PLoS One 9:e86279|
|Salhi, Hussam E; Walton, Shane D; Hassel, Nathan C et al. (2014) Cardiac troponin I tyrosine 26 phosphorylation decreases myofilament Ca2+ sensitivity and accelerates deactivation. J Mol Cell Cardiol 76:257-64|
|Longyear, Thomas J; Turner, Matthew A; Davis, Jonathan P et al. (2014) Ca++-sensitizing mutations in troponin, P(i), and 2-deoxyATP alter the depressive effect of acidosis on regulated thin-filament velocity. J Appl Physiol (1985) 116:1165-74|