Heart failure (HF) is a leading cause of morbidity and mortality worldwide. In the absence of meaningful regeneration, the adult mammalian heart undergoes pathological remodeling after myocardial infarction (MI), which contributes to the development of HF. In contrast, the neonatal heart can regenerate after injury such as MI, primarily because neonatal cardiomyocytes (CMs) respond to proliferative signaling. After birth, the vast majority of CMs withdraw from the cell cycle and lose the ability to fully regenerate the myocardium after injury. Recent evidence shows that adult mammalian CMs harbor measurable, but limited, proliferative potential. The ability of CMs to proliferate and regenerate the neonatal heart suggests a distinct molecular and cellular signature that is largely lost as CMs transition to adulthood. Understanding the mechanisms regulating CM cell cycle during developmental stages and inability to divide as observed in the adult heart represents a challenge, but may allow development of strategies for adult heart regeneration. Recently, we have identified a novel role for proto- oncogene Casitas b-lineage lymphoma (Cbl) in CM survival and death. Loss-of-Cbl function was associated with decreased CM death, increased angiogenesis and improved cardiac contractile function, demonstrating a role of Cbl in cardioprotection. Preliminary data shows that Cbl deficiency is associated with increased CM proliferation in adult mice after MI, suggesting an unrecognized role of Cbl in cardiac regeneration. Analysis of CM proliferation in neonatal mouse heart further supports this hypothesis and shows a marked increase in the rate of cycling CMs in Cbl knockout compared to wild-type (WT) mice. Cbl function is dependent on the activation of its E3 ubiquitin ligase activity, which negatively regulates receptor tyrosine kinase (RTK) signaling, and/or on its adaptor functions that mediate Cbl interaction with several molecules including phosphoinositide-3 kinase (PI3K). Our analysis of Cbl activation suggests a differential role of Cbl domains in regulating CM proliferation or death in response to external stimuli. Based on these preliminary data, we hypothesize that aberrant activation of Cbl E3 ubiquitin ligase activity negatively regulates receptor tyrosine kinase (RTK) signaling and CM proliferation, while increased Cbl interaction with PI3K mediates CM survival and proliferation and improves cardiac regeneration and function.
In aim 1, we will determine the effects of gain- and loss-of-Cbl function on CM proliferation during post-natal heart development.
In aim 2, we will investigate the impact of Cbl expression in CM proliferation following MI in both neonate and adult mice. Finally, aim 3 will define the molecular mechanisms by which Cbl affects CM proliferation and cardiac regeneration in neonatal and adult heart. The proposed experiments will provide new insights into the mechanisms whereby Cbl modulates CM proliferation and differentiation in neonatal and adult heart after MI and use our new understanding of Cbl function to uncover new approaches to enhance cardiac repair/regeneration post-MI.
Heart failure is a leading cause of morbidity and mortality worldwide. In the absence of meaningful regeneration, the adult mammalian heart undergoes pathological remodeling after myocardial infarction, which contributes to the development of heart failure. This project investigates the pathophysiological role of E3 ubiquitin ligase and adaptor molecule Cbl on cardiac regeneration after MI, which may help uncover new approaches to establish an effective therapeutic strategy for heart failure post-myocardial infarction.
