SIKs: Novel Regulators of Cardiomyocyte Plasticity

Tobacco use is a leading cause of cardiac related disease in the United States and a major contributor to the growing epidemic of heart failure.  The 5-year survival rate upon diagnosis of heart failure is ~50%, yet despite this massive unmet medical need, current drugs and treatments for heart failure have limited effects in slowing or reversing disease progression. The development of novel and efficacious heart failure therapies is desperately needed but has been particularly challenging because of our incomplete understanding of the molecular mechanisms and underlying biology that drive the pathogenesis of disease. In this proposed study, I have identified a new family of proteins called Salt Inducible Kinases (SIKs) that may represent novel drug targets in heart failure. To date, no one has studied the role of these SIK proteins in the heart and how they may contribute to the development of heart failure. In my preliminary experiments, I have shown that using a drug that targets SIKs as well as genetic engineering to remove SIKs can prevent the harmful growth in heart cells during heart failure. However, harmful cell growth is only one aspect of this disease and as such, we need to better characterize the effects of blocking SIK function in the heart. This proposal serves to accomplish just that by using chemical and genetic approaches to determine what effect SIKs have on changing the DNA and RNA landscape during heart failure. I will also use a new genetic tool called CRISPR to delete SIKs in mice to see whether this intervention can protect mice from heart failure. If my proposed studies are successful, I will gain new fundamental knowledge about how SIKs drive the development and progression of heart failure. This will contribute to our overall understanding of the underlying biology that occurs in the heart during normal and disease states and may lay the groundwork for future development of novel targeted therapies for heart failure.