Title: Promoting Cardiomyocyte Cell Cycle Activity and Cardiac Regeneration through IL13 Signaling Project Summary Close to 6 million people in the United States have heart failure (HF), which costs the nation an estimated $30.7 billion each year. HF occurs when the heart has a reduced ability to pump blood which is usually caused by diminished contractility of the myocardium. Studying cardiac regeneration in lower vertebrates provides a unique opportunity to elucidate pro-regenerative mechanisms to restore function in the heart. Interestingly, the neonatal mouse contains the ability to regenerate myocardium during its first week of life. Previous work uncovered a role for Interleukin 13 (IL13) in directly stimulating cardiomyocyte cell cycle activity and neonatal cardiac regeneration in the mouse. IL13 signals through the IL4Ra/IL13Ra1 heterodimer receptor, which is present on cardiomyocytes through adulthood. Preliminary experiments looking at the knockout of IL4Ra indicate diminished cell cycle activity and lack of cardiac regeneration when compared to wildtype littermate controls. Additionally, DNA synthesis and MI recovery were improved in 7-day old, non-regenerative mice when administered exogenous IL13. Overall, this proposal addresses the hypothesis that IL13 signaling enhances cardiomyocyte cell cycle activity and promotes cardiac regeneration in neonatal and adult mice. The following proposed experiments will investigate the cardio-regenerative potential of IL13 signaling both endogenously and exogenously.
Specific Aim 1 will test the hypothesis that IL4Ra/IL13Ra1 depletion on cardiomyocytes will inhibit cell cycle activity and cardiac regeneration. Both in vitro and in vivo experiments will assess the endogenous role of IL13 directly on cardiomyocytes. The in vivo experiments will examine regenerative potential in a novel mouse model (IL4Rafl/fl Myh6CRE) which have a cardiomyocyte-specific depletion of IL4Ra.
Aim 2 will address the hypothesis that exogenous administration of IL13 will promote cardiac regeneration and cell cycle activity in adult mice. Myocardial infarctions will be induced in 8-10 week old mice, followed by daily administration of recombinant IL13 for 4 weeks. Upon collection, cardiac function and proliferative potential will be analyzed through histology, qPCR, BrdU/EdU incorporation, and echocardiography.
Although the majority of patients who endure a heart attack survive the initial event, the resulting loss of functional cardiomyocytes and the inability of the adult heart to regenerate leads to the development of heart failure. Interleukin 13 (IL13) has been found to promote cardiomyocyte proliferation and cardiac regeneration in neonatal mice; however, the underlying signaling pathways mediating these effects are not understood. This proposal aims to investigate the impact of endogenous and exogenous IL13 signaling on cardio-regenerative potential in neonatal and adult mice.
