The central theme of this PPG is to identify novel signaling molecules and pathways that contribute to the pathogenesis of heart failure (HF) after cardiac injury and also to study potential intersecting signaling and cellular mechanisms for repair of failing myocardium. The proposal specifically will identify critical molecular mechanisms that cause the cardiac injury that leads to HF and determine cellular and molecular mechanisms that promote repair of the damaged heart. The latter will involve novel pathways involved in the generation of new myocytes. The unifying theme and ultimate goal of our group's application is that identification of molecular and cellular pathways involved in either cardiac injury or repair will lead to novel translational studies with a shared PPG vision towards identifying new therapeutic strategies for reversing HF and improving outcomes, which is something desperately needed as the incidence of this devastating disease continues to rise. Our efforts will come from multiple but complimentary directions and all investigators will use newly developed mouse models to test individual project hypotheses all focused on the theme of novel mechanisms of cardiac injury and repair. This focused PPG is being led by project leaders who are distinguished scientists in the HF arena with a long history of productivity, and who have recently been brought together in the city of Philadelphia. This has led to natural collaborations that now form the basis for putting together four integrative projects around our central theme that is particularly suited for a PPG application. The themes of each project are: Project 1 (Koch) will study how the novel nuclear activity of G protein-coupled receptor kinase-5 (GRK5) alters myocardial responses to stressors that cause hypertrophy, injury and eventually lead to HF;Project 2 (Feldman) will investigate the role of specific adenosine receptor subtypes in cardiac injury induction and protection including the study of novel mechanistic involvement of G protein signaling and calcium (Ca2+);Project 3 (Houser) will study the links between Ca2+ entry through the L-type Ca2+ channel, Ca2+ overload of the sarcoplasmic reticulum (SR), myocyte death from apoptosis and necrosis and HF. These studies will employ a novel mouse model in which Ca2+ influx can be altered. This study will also determine if myocyte death induced by excess Ca2+ influx induces an increase in stem cell derived new myocyte formation to regenerate cardiac tissue;and Project 4 (Force) involves determining mechanistically how tyrosine kinase inhibitors used as cancer therapeutics cause a novel reversible cardiomyopathy that may involve alterations in cellular energetics as well as a loss of the heart's repair and regenerative properties. Importantly, all Project leaders have expertise in translating their basic results, which represents a real strength of our program.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL091799-03
Application #
7797573
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Schwartz, Lisa
Project Start
2008-05-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$2,329,752
Indirect Cost
Name
Thomas Jefferson University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Cannavo, Alessandro; Rengo, Giuseppe; Liccardo, Daniela et al. (2017) ?1-Blockade Prevents Post-Ischemic Myocardial Decompensation Via ?3AR-Dependent Protective Sphingosine-1 Phosphate Signaling. J Am Coll Cardiol 70:182-192
Schumacher, Sarah M; Koch, Walter J (2017) Noncanonical Roles of G Protein-coupled Receptor Kinases in Cardiovascular Signaling. J Cardiovasc Pharmacol 70:129-141
Waldschmidt, Helen V; Homan, Kristoff T; Cato, Marilyn C et al. (2017) Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine. J Med Chem 60:3052-3069
Eisner, VerĂ³nica; Cupo, Ryan R; Gao, Erhe et al. (2017) Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity. Proc Natl Acad Sci U S A 114:E859-E868
Bouley, Renee; Waldschmidt, Helen V; Cato, M Claire et al. (2017) Structural Determinants Influencing the Potency and Selectivity of Indazole-Paroxetine Hybrid G Protein-Coupled Receptor Kinase 2 Inhibitors. Mol Pharmacol 92:707-717
Guo, Shuchi; Carter, Rhonda L; Grisanti, Laurel A et al. (2017) Impact of paroxetine on proximal ?-adrenergic receptor signaling. Cell Signal 38:127-133
Woodall, Benjamin P; Woodall, Meryl C; Luongo, Timothy S et al. (2016) Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy. J Biol Chem 291:21913-21924
Hullmann, Jonathan; Traynham, Christopher J; Coleman, Ryan C et al. (2016) The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development. Pharmacol Res 110:52-64
Wasilewski, Melissa A; Grisanti, Laurel A; Song, Jianliang et al. (2016) Vasopressin Type 1A Receptor Deletion Enhances Cardiac Contractility, ?-Adrenergic Receptor Sensitivity and Acute Cardiac Injury-induced Dysfunction. Clin Sci (Lond) :
Zhou, Jibin; Ahmad, Firdos; Lal, Hind et al. (2016) Response by Zhou et al to Letter Regarding Article, ""Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy"". Circ Res 119:e29-e30

Showing the most recent 10 out of 148 publications