The central hypothesis that underlies this project is that the progressive decline in cardiac function seen in patients with non-ischemic heart failure is a reflection of the post-translational modification of cardiac contractile proteins, specifically the thin filaments proteins, troponin I, T and the regulatory myosin light chain (MLC2). To test this hypothesis, we will collect myocardial samples from two distinct groups: i) patients with and without diabetes undergoing coronary bypass surgery, ii) patients with idopathic dilated cardiomyopathy undergoing cardiac surgery (either ventricular modification or tranplantation) and, as controls patients with normal ventricular function undergoing valve replacement or bypass surgery. We will test the extent of myofilament dysfunction in skinned cells and determine whether dephosphorylation by PP1A will eliminate differences between sample groups (aim 1). Next, we will correlate myofilament function and clinical status with contractile protein isoform distribution and phosphorylation status, paying particular attention to the components of the troponin complex and the regulatory myosin light chain (aim 2). Finally, sarcomeric proteins will be extracted in the context of the pathologic cell and replaced with recombinant proteins that have been modified so as to recapitulate the non-pathologic situation (aim 3). The overall goal of the project is to identify specific and modifiable biochemical interfaces that might allow rational treatment of nonischemic cardiac muscle dysfunction.
| Thoemmes, Stephen F; Stutzke, Crystal A; Du, Yanmei et al. (2014) Characterization and validation of new tools for measuring site-specific cardiac troponin I phosphorylation. J Immunol Methods 403:66-71 |
| Walker, Lori A; Buttrick, Peter M (2013) The right ventricle: biologic insights and response to disease: updated. Curr Cardiol Rev 9:73-81 |
| Walker, Lori A; Fullerton, David A; Buttrick, Peter M (2013) Contractile protein phosphorylation predicts human heart disease phenotypes. Am J Physiol Heart Circ Physiol 304:H1644-50 |
| Vitello, Andrea M; Du, Yanmei; Buttrick, Peter M et al. (2012) Serendipitous discovery of a novel protein signaling mechanism in heart failure. Biochem Biophys Res Commun 421:431-5 |
| Ambardekar, Amrut V; Buttrick, Peter M (2011) Reverse remodeling with left ventricular assist devices: a review of clinical, cellular, and molecular effects. Circ Heart Fail 4:224-33 |
| Walker, John S; Walker, Lori A; Margulies, Ken et al. (2011) Protein kinase A changes calcium sensitivity but not crossbridge kinetics in human cardiac myofibrils. Am J Physiol Heart Circ Physiol 301:H138-46 |
| Belin, Rashad J; Sumandea, Marius P; Sievert, Gail A et al. (2011) Interventricular differences in myofilament function in experimental congestive heart failure. Pflugers Arch 462:795-809 |
| Ambardekar, Amrut V; Walker, John S; Walker, Lori A et al. (2011) Incomplete recovery of myocyte contractile function despite improvement of myocardial architecture with left ventricular assist device support. Circ Heart Fail 4:425-32 |
| Walker, John S; Li, Xiaotao; Buttrick, Peter M (2010) Analysing force-pCa curves. J Muscle Res Cell Motil 31:59-69 |
| Walker, Lori A; Buttrick, Peter M (2009) The right ventricle: biologic insights and response to disease. Curr Cardiol Rev 5:22-8 |
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