Grant: Project Grant

Heart transplantation is the best treatment for individuals with end stage heart failure. However, the endothelial cells that line the blood vessels of the heart transplant are attacked by the recipient's immune system. Despite modern immunosuppression drugs, the injury to the blood vessels accumulates resulting in narrowing of the major arteries that supply blood and nutrients to the heart, and loss of the small feeder blood vessels of the heart muscle. In time, the heart muscle of the transplant fails, in part because of the lack of blood supply. We seek to understand the repair response undertaken by the endothelial cells that line the blood vessels of a heart transplant. We will focus on one repair molecule, Apelin, that we recently identified to play a critical role in the development of transplant vascular disease in both mice and humans. We will determine if administration of the candidate molecule (drug), Apelin, blunts narrowing of the major arteries in a heart transplant model. Currently, little is known about the repair response mounted by the blood vessel cells in the transplant organ. Since mouse models of heart transplantation faithfully replicate the key features of injury to blood vessels of human heart transplants, we will study the vascular repair response in these mouse models in detail. We will exploit mutant mice that lack endothelial cell expression of specific genes-of-interest as heart donors to determine if the genes are required to mount the repair response. Our group has identified a major role for Apelin to protect against transplant vascular disease, and is the first group to find a potential treatment. We have assembled a unique set of mutant mice to further test and extend our findings, and collaborators with specialized expertise in genetics, aging, and apelin-like drug development. These collaborations aim to bring advances in diagnostics and therapeutics arising from the work into the clinic.