b1AR-mediated EGFR transactivation in the heart

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 DESCRIPTION (provided by applicant): Heart failure (HF) is a progressive disease affecting millions of people in the U.S. with the care of these patients costing billions of dollars annually While patient symptoms and mortality have been reduced with the use of neurohormone receptor antagonists, such as β-blockers, their long-term impact on cardiac remodeling and patient lifespan is limited. G protein-coupled receptor (GPCR) signaling pathways have been shown for some time to be tunable, wherein protective pathways (often β-arrestin-dependent) may be selected for through biased ligands, while deleterious pathways (usually G protein-dependent) are simultaneously inhibited. However, there has been a disappointing lack of progress in the development of biased ligands for β- adrenergic receptors (βARs) in particular, which have been shown to relay cardioprotective outcomes via β- arrestin-dependent transactivation of epidermal growth factor receptor (EGFR). Over the last few years we have extensively characterized the subcellular signaling, transcriptional and cardiac remodeling responses that occur in response to both acute and chronic EGFR transactivation in cardiomyocytes and in whole heart following β1AR stimulation. Our studies have highlighted the potential therapeutic benefit of β1AR-mediated EGFR transactivation and provided rationale for its pursuit as a HF treatment strategy, however lack of specific tools has prevented the execution of definitive studies. In particular, bona fide β1AR-specific βarr/EGFR- biased ligands with enhanced efficacy, and that do not impact G protein-dependent signaling, do not exist. Thus, EGFR transactivation studies to date have relied upon EGFR inhibition in the presence of βAR stimulation to indirectly measure its impact on cardiomyocyte/cardiac signaling, transcription and survival outcomes. Additionally, EGFR knockout animals are not viable, thereby preventing assessment of EGFR function in adult models of HF without the use of pharmacologic inhibitors that introduce selectivity and toxicity issues. With these issues in mind, we have begun to test pepducins, small peptide fragments of the intracellular loops of GPCRs that allosterically induce biased signaling, specifically for the β1AR with the intent to drive EGR transactivation in the absence of G protein activation. These new molecular tools will allow positive characterization of β1AR-mediated EGFR transactivation in cardiomyocytes for the first time, without the reliance upon pharmacological inhibitors. Additionally, we have generated a cardiomyocyte-specific inducible EGFR deletion mouse model that will definitively establish the impact of EGFR signaling in the heart in response to βAR stimulation, as well as in the context of more broad forms of HF development. These studies will therefore provide the first direct assessment of the importance of cardiomyocyte-expressed EGFR during HF, as well as generate novel and potentially therapeutic agents with which to specifically engage β1AR-depedent EGFR transactivation to promote survival signaling and reduce detrimental structural and functional outcomes during HF.