Cardiomyocyte-Specific Modified mRNA for Myocardial Regeneration in a Porcine Myocardial Infarction Model
Description: Mammalian cardiomyocytes (CMs) exit cell cycle within a few days after birth thus, the regenerative capacity of adult mammalian hearts is extremely limited. The loss of CMs due to myocardial infarction (MI) and insufficient CM regenerative capacity often leads to end-stage congestive heart failure. A recent study reported that mouse pyruvate kinase muscle isoenzyme 2 (mPkm2), delivered by a safe, transient, and nonimmunogenic cardiomyocyte specific modified mRNA translation system (SMRTs), successfully regulated CM cell cycle, promoted cardiac regeneration, and preserved heart function in a mouse MI model. However, whether human PKM2 (hPKM2) overexpression via SMRTs could reactivate CM cell cycle and improve cardiac function in the porcine with MI remains unknown, impeding the clinical translation of this cutting-edge technology. In the proposal, I will evaluate if the cell cycle can be reactivated by hPKM2 overexpression via SMRTs in mouse primary CM and human iPSC-CM. I will also utilize hPKM2 SMRTs on porcine hearts after induced MI to test the translation efficiency and cell specificity of this system. I will also monitor heart function, evaluate proliferation and apoptosis of cardiomyocytes, measure cardiac fibrosis, and assess the overall therapeutic effects of hPKM2 SMRTs. The results from in vitro human cells and large animal studies will evaluate the therapeutic effects of hPKM2 SMRTs, providing insights for the clinical translation of this modRNA-based therapy for MI.
Funder: American Heart Association
Amount: $65,110
Funding type: training
Funder scheme: Predoctoral Fellowship
Start date: 2023-01-01
End date: 2024-12-31
Investigators: Jiacheng Sun, Jiacheng Sun
Institution: University of Alabama at Birmingham
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 1
Funder award ID: 23PRE1025367
OpenAlex ID: G3273761972