Grant: Project Grant

Cardiac diseases are the leading cause of death in developed countries. Over time, as hearts age or become senescent, adverse remodelling that is initially beneficial, progressively leads to reduced cardiac functioning. Our research aims to understand the molecular mechanisms that underlie this remodeling and repair. Circular RNAs are closed continuous loops of RNA that were recently detected in eukaryotic cells, and may affect cell physiology through a variety of mechanisms. Our work revealed that the circular RNA circ-Dnmt1 is tightly associated with senescent or aged heart. We thus hypothesize that circular RNAs may regulate cell aging and tissue repair by binding to protein regulators of cardiac senescence. To test our hypothesis, we will modify cardiac fibroblasts so that they express more of the circular RNAs in question. We can also use the reverse approach to silence circular RNA expression, and observe the changes in function. Using these two approaches, in conjunction with standard experimental models, we can better understand the function of circular RNAs in cardiac senescence. There are two unique aspects to our proposed study. Firstly, we are among the first to produce a stable expression construct allowing long-term studies of the circular RNAs. The second unique approach is our inhibitor system that is designed to block the function of individual circular RNAs in both cell and animal models. These allow us to specifically study individual circular RNAs, and better understand any causal relationships. Our proposed experiments will help us explore the regulatory roles of circular RNAs in both cardiac aging and other cellular repair contexts. The agents developed may be used as tools in understanding the role of circular RNAs in heart development, aging, disease-associated injury and tissue regeneration. With these approaches, we hope to design therapies to intervene against the adverse remodeling associated with age-related heart disease.