Grant: Project Grant

A heart attack (Myocardial Infarction or MI) is a common and severe condition where a clot blocks a heart blood vessel, causing tissue death and scarring. Reperfusion therapy, which restores blood flow, is the most effective treatment but can also cause reperfusion injury, contributing up to half of the final scar size and increasing the risk of death. New therapies are needed. Scientists have discovered the hearts circadian mechanism, a natural timekeeping clock that regulates its function. Our studies in mice show that this circadian mechanism affects how the hearts genes, proteins, strength, and energy function differently throughout the day and night. Disruptions to this mechanism, like those from shift work, can lead to heart issues. We will use this knowledge to target the circadian mechanism in the heart by administering tiny new drugs (small molecule modulators), offering promising ways to better understand and improve cardiac repair. We have three main goals. First, we will focus on a circadian component called REV-ERB with a tiny drug, SR9009, given during reperfusion. Our early data from mice show that this reduces the harmful NLRP3 inflammasome, a complex activated by reperfusion that causes damaging inflammation in the heart. By targeting it, we reduce reperfusion injury, leading to smaller scars and better outcomes. Second, we'll target another circadian mechanism component, ROR with SR2211 given at reperfusion, which preliminary mouse data suggests improves cardiac repair by downregulating the harmful cytokine IL-17. Lastly, we'll study ROR's role in chronic cardiac hypertrophy to better understand its effects. These studies, focusing on the circadian mechanism in the heart, will greatly enhance our understanding of heart disease and lead to "Molecules to Circadian Medicine," improving treatments and helping patients to live longer, healthier lives.