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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL104352-02
Application #
8247680
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2011-04-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$191,250
Indirect Cost
$66,250
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
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