Cardiomyocyte loss following myocardial infarction is a major cause of chronic heart failure (CHF), and therapies that protect or regenerate cardiomyocytes are needed to address this unmet clinical need. Numerous pre-clinical and clinical studies have revealed the importance of ErbB receptor-mediated signaling in both cardioprotection and cardiac regeneration. Thus, engagement of ErbB receptors is an emerging and potentially translatable strategy to treat CHF. We have engineered novel, bivalent ErbB ligands based on the crystal structures of ErbB receptors. The bivalent ligand approach uses two receptor binding domains covalently linked in a spatially constrained manner, such that each domain should be capable of binding separate receptors in a dimerized conformation. By capitalizing on receptor-ligand affinity interactions, these bivalent ligands can bias ErbB recepto signaling to activate downstream pathways preferentially compared to native ErbB ligands, unlocking new therapeutic opportunities. As shown in this proposal, we have now demonstrated the promise of this approach by showing that a bivalent NRG-1 (NN) induces a greater degree of ErbB4 phosphorylation in the heart compared to native NRG-1, resulting in functional cardioprotective benefit in vitro and in vivo in a mouse model. Moreover, NN induces cytostatic or apoptotic phenotypes in cancer cells in which native NRG-1 has pro-neoplastic effects. Thus, NN may lead to greater benefits in CHF treatment than native NRG-1, and understanding the mechanisms of this approach could lead to novel approaches to CHF therapy.
Our Specific Aims are:
Aim 1 : To test the hypothesis that cardiomyocyte NRG-1b signaling can be biased to differentially activate molecular intracellular pathways relevant to CHF.
Aim 2 : To test the hypothesis that protein engineering applied to ErbB receptor ligands can differentially regulate cardiomyocyte ErbB receptor signaling.
Aim 3 : To test the hypothesis that bivalent NRG-1b (NN) is a superior CHF therapeutic compared to native NRG-1b.
Congestive Heart Failure is an epidemic problem in the United States, and there are insufficient treatment options for heart failure patients. By rational protein design, this project will determine if new proteins can benefit the heart. This project has the potential to reveal new treatments for patients with heart failure.
|Lee, Richard T; Walsh, Kenneth (2016) The Future of Cardiovascular Regenerative Medicine. Circulation 133:2618-25|
|Mahmoud, Ahmed I; Lee, Richard T (2016) Adrenergic function restoration in the transplanted heart: a role for neural crest-derived cells. Cardiovasc Res 109:348-9|
|Dotimas, James R; Lee, Austin W; Schmider, Angela B et al. (2016) Diabetes regulates fructose absorption through thioredoxin-interacting protein. Elife 5:|
|O'Meara, Caitlin C; Lee, Richard T (2015) Peering Into the Cardiomyocyte Nuclear Epigenetic State. Circ Res 117:392-4|
|O'Meara, Caitlin C; Wamstad, Joseph A; Gladstone, Rachel A et al. (2015) Transcriptional reversion of cardiac myocyte fate during mammalian cardiac regeneration. Circ Res 116:804-15|
|Mahmoud, Ahmed I; O'Meara, Caitlin C; Gemberling, Matthew et al. (2015) Nerves Regulate Cardiomyocyte Proliferation and Heart Regeneration. Dev Cell 34:387-99|
|Jiang, Jianming; Burgon, Patrick G; Wakimoto, Hiroko et al. (2015) Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis. Proc Natl Acad Sci U S A 112:9046-51|
|Alvarez, Luis M; Rivera, Jaime J; Stockdale, Linda et al. (2015) Tethering of Epidermal Growth Factor (EGF) to Beta Tricalcium Phosphate (Î²TCP) via Fusion to a High Affinity, Multimeric Î²TCP-Binding Peptide: Effects on Human Multipotent Stromal Cells/Connective Tissue Progenitors. PLoS One 10:e0129600|
|Bryant, Donald Marion; O'Meara, Caitlin Claire; Ho, Nhi Ngoc et al. (2015) A systematic analysis of neonatal mouse heart regeneration after apical resection. J Mol Cell Cardiol 79:315-8|
|Loffredo, Francesco S; Nikolova, Andriana P; Pancoast, James R et al. (2014) Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium. Circ Res 115:97-107|
Showing the most recent 10 out of 11 publications