Cellular and Molecular Regulation of Mammalian Heart Regeneration
Heart failure is the leading cause of death in the world due to the inability of the adult mammalian heart to regenerate following injury. Lower vertebrates, such as zebrafish are capable of complete and efficient regeneration of the myocardium following injury. Similarly, we demonstrated that neonatal mice are capable of regenerating their hearts within a short period after birth but lose this potential in the first week of life. Adult mammals lack this cardiac regeneration potential, thus our overarching goal in the laboratory is to dissect the molecular underpinnings of regeneration in the neonatal heart so that we can explore potential avenues to activate this process in adult humans.
Our goals are to identify the transcriptional and epigenetic networks that govern cardiomyocyte dedifferentiation and proliferation during regeneration. These studies could aid in converting adult cardiomyocytes to a more proliferative and regenerative state. In addition, we aim to identify the microenvironment signals that regulate mammalian heart regeneration by studying the interplay of nerves as well as extracellular factors during mammalian heart regeneration. We use multidisciplinary approaches including genomics, proteomics, and mouse genetics in addition to molecular and cellular technologies to address these questions.
- Nerve Guidance of Heart Regeneration
- Transcriptional Regulation of Myocyte Division
- Proteomics of Heart Regeneration
Mechanisms of Nerve-Guidance of Heart Regeneration
Nerves have been shown to play a critical role in regeneration across different species. The role of nerve function during regeneration underscores the importance of signals from the microenvironment for guiding a proper regenerative response. Recently, we demonstrated that regeneration of the neonatal mouse heart is attenuated by pharmacological or mechanical suppression of the cholinergic nerve function. We also demonstrated that nerve-modulated growth factors as Neuregulin 1 (NRG1) and Nerve Growth Factor (NGF) contribute to nerve-mediated heart regeneration. In addition, we showed that nerves fine-tune the inflammatory and immune response following injury. This indicates that nerves are important for mediating a full regenerative response following injury. Our goal is to determine the mechanisms by which nerves contribute to heart regeneration through identifying specific factors derived from nerves that modulate the process of myocardial regeneration. In addition, we aim to dissect the role of the cholinergic anti-inflammatory pathway during regeneration.
Transcriptional and Epigenetic Regulation of Cardiomyocyte Pr0liferation
Cardiomyocyte proliferation is the major source of newly formed myocardium during neonatal heart regeneration. However, mammalian cardiomyocytes exit the cell cycle shortly after birth, and thus the adult mammalian heart fails to regenerate in response to injury. Thus, identifying the transcriptional and epigenetic networks that govern cardiomyocyte dedifferentiation and proliferation during regeneration could aid in converting adult cardiomyocytes to a more proliferative and regenerative state. Our goal is to the explore genomic and epigenetic pathways that are important for regulating cardiomyocyte cell cycle activity through transcriptional regulators of chromatin structure. These results could provide new potential therapeutic strategies for cardiovascular diseases.
Quantitative Mass Spectrometry and Proteomics of Heart Regeneration
In order to identify novel proteins that mediate cardiac regeneration, we will employ large scale proteomics to map out the cardiac regeneration proteome. This will unravel the role of novel proteins and their post translational modifications during cardiac regeneration, and will allow us to identify the mechanisms that mediate cardiac regeneration pathways.