# Targeting Cbl for Cardiac Repair Post-Myocardial Infarction

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $495,392

## Abstract

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 ...

## Key facts

- **NIH application ID:** 9852370
- **Project number:** 5R01HL145177-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** AbdelKarim Sabri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $495,392
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852370

## Citation

> US National Institutes of Health, RePORTER application 9852370, Targeting Cbl for Cardiac Repair Post-Myocardial Infarction (5R01HL145177-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852370. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*