Over the last decade+ that this R01/R37 has been funded, we have defined a key role for G protein-coupled receptor (GPCR) kinase 2 (GRK2 or pARK1) in not only the dysregulation of p-adrenergic receptor signaling in the injured/stressed heart but also in cardiac functions that are independent from GRK2's actions on GPCRs. The data that we have published to date from this MERIT Award as well as ongoing research strongly argue for GRK2 being a nodal regulator of cardiac injury and pathogenesis of heart failure (HF). Our original Aims are still valid and are formulated to test the Central Hypothesis that GRK2 plays a critical role in pathological hypertrophy, ischemic injury and HF via mechanisms beyond GPCR desensitization. Our original Specific Aims are:
Specific Aim 1 : To determine whether non-GPCR functions of GRK2 play a facilitative role in the pathogenesis of maladaptive cardiac hypertrophy and LV remodeling.
Specific Aim 2 : To investigate the role of GRK2 in dysfunctional myocardial glucose uptake after ischemia and to determine the cellular mechanisms of how GRK2 regulates glucose metabolism and insulin signaling.
Specific Aim 3 : To determine whether viral-mediated gene transfer of a micro-RNA that targets and silences GRK2 expression (miGRK2) offers a novel therapeutic strategy for pathological hypertrophy and ischemic HF. With the two years left on the current period we will continue these studies testing our central hypothesis and will also embark on three new aims that are natural extensions of the above Aims and are exciting avenues uncovered by new data. These new Specific Aims are:
Specific Aim 4 : To determine the role of the amino-terminus (RGS domain) of GRK2 in cardiac hypertrophy.
Specific Aim 5 : To study the mechanistic role of MAP kinase regulation of GRK2 {at residue Ser670) in vivo through characterization and study of a novel GRK2-S670A knock-in mice.
Specific Aim 6 : To determine the role of GRK2 in the cardiac fibroblast during cardiac injury. These studies will continue to elucidate novel aspects of GRK2 biology in the heart as a nodal regulator of pathogenesis and a viable therapeutic target.

Public Health Relevance

Since expression levels and activity of GRK2 are elevated in failing myocardium including in human heart failure (HF), uncovering novel mechanistic aspects of this GRK using our unique animal models and molecular reagents will lead to a broader understanding of the pathogenesis of hypertrophic and ischemic cardiac dysfunction. Moreover, our translational studies described will prove that GRK2 is an innovative theraneutic taraftt for HF

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37HL061690-17
Application #
8822588
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Adhikari, Bishow B
Project Start
2014-07-01
Project End
2019-05-31
Budget Start
2014-07-01
Budget End
2015-05-31
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Temple University
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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
Woodall, Meryl C; Woodall, Benjamin P; Gao, Erhe et al. (2016) Cardiac Fibroblast GRK2 Deletion Enhances Contractility and Remodeling Following Ischemia/Reperfusion Injury. Circ Res 119:1116-1127
Waldschmidt, Helen V; Homan, Kristoff T; Cruz-Rodríguez, Osvaldo et al. (2016) Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors. J Med Chem 59:3793-807
Cannavo, Alessandro; Liccardo, Daniela; Eguchi, Akito et al. (2016) Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases. Nat Commun 7:10877
Cannavo, Alessandro; Liccardo, Daniela; Lymperopoulos, Anastasios et al. (2016) β Adrenergic Receptor Kinase C-Terminal Peptide Gene-Therapy Improves β2-Adrenergic Receptor-Dependent Neoangiogenesis after Hindlimb Ischemia. J Pharmacol Exp Ther 356:503-13
Traynham, Christopher J; Hullmann, Jonathan; Koch, Walter J (2016) ""Canonical and non-canonical actions of GRK5 in the heart"". J Mol Cell Cardiol 92:196-202
Khan, Mohsin; Koch, Walter J (2016) c-kit+ Cardiac Stem Cells: Spontaneous Creation or a Perplexing Reality. Circ Res 118:783-5
Rengo, Giuseppe; Pagano, Gennaro; Filardi, Pasquale Perrone et al. (2016) Prognostic Value of Lymphocyte G Protein-Coupled Receptor Kinase-2 Protein Levels in Patients With Heart Failure. Circ Res 118:1116-24
Schumacher, Sarah M; Gao, Erhe; Cohen, Maya et al. (2016) A peptide of the RGS domain of GRK2 binds and inhibits Gα(q) to suppress pathological cardiac hypertrophy and dysfunction. Sci Signal 9:ra30
Trappanese, Danielle M; Liu, Yuchuan; McCormick, Ryan C et al. (2015) Chronic β1-adrenergic blockade enhances myocardial β3-adrenergic coupling with nitric oxide-cGMP signaling in a canine model of chronic volume overload: new insight into mechanisms of cardiac benefit with selective β1-blocker therapy. Basic Res Cardiol 110:456

Showing the most recent 10 out of 53 publications