Characterizing the monocytic origins of fibroblast progenitor cells and how we can use this information for myocardial therapies

Scar tissue is a common feature in many types of heart disease and can lead to the reduced ability of the heart to pump blood, called heart failure. Heart failure continues to carry a 3-year mortality of up to 50% and as such, is an important target for novel, effective therapies. In this proposal, we outline how our knowledge of scar tissue development can potentially be used in therapies to prevent or treat heart failure. The primary focus of our research is a type of cell called fibrocytes. Fibrocytes are important in the development of heart failure because they move from blood into injured tissues, where they deposit scar tissue. Some scientists have tried to target fibrocytes for therapies, but the results to date have not showed much promise. We are using a different approach than those previously tested: we believe that by targeting the cells that become fibrocytes, we can reduce or even prevent the development of scar tissue in the heart. Fibrocytes develop from a cell type called monocytes, which can be specifically targeted by changing the way certain drugs are delivered to the body. Monocytes circulate in the blood and take up virtually any objects they identify as foreign (e.g. bacteria). By packaging drugs as foreign objects, we are able to deliver them specifically to monocytes. We use drugs that kill monocytes with minimal to no toxic effects on other cells. In doing so, we are able to kill the cells that give rise to fibrocytes. Studies that use this method of monocyte targeting have being effective in reducing scar tissue in other organs like the kidneys; however, they have never been tested in heart failure. Using an animal model of heart failure, we will be testing how killing monocytes affects the development of scar tissue in the heart. We will specifically be looking at how getting rid of monocytes affects fibrocytes and whether this therapy can be used as a treatment for already established scar tissue as well as a preventative therapy.