Cardiac myosin light chain kinase function in huma.. (hES-Cardio)
Cardiac myosin light chain kinase function in human pluripotent stem cell derived cardiomyocytes
Start date: Sep 14, 2012,
End date: Dec 31, 2016
The main hurdle to the effective use of stem cell derived cardiomyocytes (hESC-CMs and hIPSC-CMs) in drug toxicology screening and transplantation therapy is their embryonic nature. It is recognised that hESC-CM and hIPSC-CM are immature and undergo limited maturation in the laboratory. This creates problems as the cells may not display appropriate responses to target drugs in toxicology screening and may not be suitable for transplantation into the damaged heart. The research outlined in this proposal will begin to address these issues.The aim of my proposal is to study the function and regulation of the recently discovered cardiac myosin light chain kinase (MLCK) and its downstream targets, regulatory myosin light chain (MLC) proteins. Evidence suggests that cardiac MLCK is responsible for modulating cardiomyocyte contractility. In studying the function of cardiac MLCK I aim to generate hESC-CM and hIPSC-CM with an increased structural maturity, which will be more suitable for drug toxicology screening.Importantly, the study of cardiac MLCK also has clinical relevance. Expression of cardiac MLCK is downregulated in the hearts of rats that suffered induced myocardial infarction, and when used to treat these animals, upregulation of the gene can improve cardiac output. Investigation of cardiac MLCK function in human cardiomyocytes in this proposal may provide insights into a potential role for cardiac MLCK in the treatment of heart attack patients.Finally, the proposed research will also highlight the potential of hESC-CM and hIPSC-CM as models to study the basic biology of the human heart.
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