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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL114940-05
Application #
9270577
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2013-09-01
Project End
2018-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Ohio State University
Department
Physiology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Tikunova, Svetlana B; Cuesta, Andres; Price, Morgan et al. (2018) 3-Chlorodiphenylamine activates cardiac troponin by a mechanism distinct from bepridil or TFP. J Gen Physiol :
Saad, Nancy S; Elnakish, Mohammad T; Brundage, Elizabeth A et al. (2018) Assessment of PKA and PKC inhibitors on force and kinetics of non-failing and failing human myocardium. Life Sci 215:119-127
Martin-Garrido, Abel; Biesiadecki, Brandon J; Salhi, Hussam E et al. (2018) Monophosphorylation of cardiac troponin-I at Ser-23/24 is sufficient to regulate cardiac myofibrillar Ca2+ sensitivity and calpain-induced proteolysis. J Biol Chem 293:8588-8599
Markowitz, Joseph; Wang, Jiang; Vangundy, Zach et al. (2017) Nitric oxide mediated inhibition of antigen presentation from DCs to CD4+ T cells in cancer and measurement of STAT1 nitration. Sci Rep 7:15424
Li, Ning; Hansen, Brian J; Csepe, Thomas A et al. (2017) Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure. Sci Transl Med 9:
Lang, Sarah E; Stevenson, Tamara K; Schatz, Tabea M et al. (2017) Secondary phosphorylation in myocytes expressing FLAG-tagged and non-tagged phospho-mimetic cardiac troponin I. Data Brief 15:562-566
Lang, Sarah E; Stevenson, Tamara K; Schatz, Tabea M et al. (2017) Functional communication between PKC-targeted cardiac troponin I phosphorylation sites. Arch Biochem Biophys 627:1-9
Chung, Jae-Hoon; Biesiadecki, Brandon J; Ziolo, Mark T et al. (2016) Myofilament Calcium Sensitivity: Role in Regulation of In vivo Cardiac Contraction and Relaxation. Front Physiol 7:562
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
Shettigar, Vikram; Zhang, Bo; Little, Sean C et al. (2016) Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease. Nat Commun 7:10794

Showing the most recent 10 out of 31 publications