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 ?ARK1) in not only the dysregulation of ?-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 therapeutic target 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 #
5R37HL061690-18
Application #
8878330
Study Section
Special Emphasis Panel (NSS)
Program Officer
Adhikari, Bishow B
Project Start
2014-07-01
Project End
2019-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
18
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Temple University
Department
Type
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
de Lucia, Claudio; Gambino, Giuseppina; Petraglia, Laura et al. (2018) Long-Term Caloric Restriction Improves Cardiac Function, Remodeling, Adrenergic Responsiveness, and Sympathetic Innervation in a Model of Postischemic Heart Failure. Circ Heart Fail 11:e004153
Grisanti, Laurel A; Schumacher, Sarah M; Tilley, Douglas G et al. (2018) Designer Approaches for G Protein-Coupled Receptor Modulation for Cardiovascular Disease. JACC Basic Transl Sci 3:550-562
de Lucia, Claudio; Eguchi, Akito; Koch, Walter J (2018) New Insights in Cardiac ?-Adrenergic Signaling During Heart Failure and Aging. Front Pharmacol 9:904
Cannavo, Alessandro; Koch, Walter J (2018) GRK2 as negative modulator of NO bioavailability: Implications for cardiovascular disease. Cell Signal 41:33-40
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
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
Guo, Shuchi; Carter, Rhonda L; Grisanti, Laurel A et al. (2017) Impact of paroxetine on proximal ?-adrenergic receptor signaling. Cell Signal 38:127-133
Cannavo, Alessandro; Koch, Walter J (2017) Targeting ?3-Adrenergic Receptors in the Heart: Selective Agonism and ?-Blockade. J Cardiovasc Pharmacol 69:71-78
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

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