The adaptational response of the heart to a pathologic stress is a complex process that reflects the nature, severity and duration of the insult. Many of these cellular changes have a negligible impact on the integrated performance of the heart however some have been shown to be critically important in moderating force generation and relaxation, properties that define integrated cardiac performance. In this proposal we propose to develop a unique diagnostic tool, a phosphoprotein antibody chip that can be used to define potentially tractable alterations in the maladaptive heart that might be amenable to targeted therapy. Two complementary approaches will be imbedded in this chip, the first is the inclusion of existing antibody probes that target signaling pathways known to be altered in maladaptive heart disease and the second will be the development and inclusion of a series of novel phosphoantibodies directed against specific sarcomeric protein sites that have been shown to have functional significance in reconstituted myofibrillar preparations. Finally we will validate this diagnostic tool using tissue from well characterized animal models as well as from humans with clinical heart failure.
Heart failure is a leading cause of death and disability in Western society, affecting more than 5 million Americans. The disease affects many aspects of the heart but one fundamental defect resides at the level of the contractile elements within the muscle. Changes in myofilament protein status underlie functional changes in the heart. The goal of this proposal is to design a diagnostic tool (a protein antibody chip) that will allow an assessment of disease status based on the myofilament protein profile. Furthermore, this tool may also be used to identify potentially tractable features of the muscle that lead to novel therapies.
|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; 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; 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|