Project Summary / Abstract Inflammation is a major contributor to coronary artery disease (CAD), the process that involves build-up of plaques within the coronary arteries. These plaques result in heart attacks and chronic heart disease due to poor blood supply to the heart muscle, and thus they explain more worldwide morbidity and mortality than any other pathological process. Macrophages are cells of the immune system that are central components of these plaques in CAD. We have discovered critical factors that determine whether macrophages become inflammatory, associated with worse disease, or regulatory, which can reduce disease, and will define whether or not one of these central factors, Skap2, governs the switch from the inflammatory to the regulatory state in plaques. With a clear understanding of what determines macrophage behavior in the plaque, we aspire ultimately to point to new therapies that make macrophages more regulatory—stopping them from driving inflammation—and instead inducing them to heal or stabilize plaques in order to reduce the burden of CAD. This project is innovative and impactful in several ways. First, as opposed to much prior work done on macrophage cell lines or cells derived in vitro, it will define the role of key macrophage molecules in this switch from inflammatory to regulatory function in macrophages isolated directly from the plaque. Second, because translating finding to humans is paramount, it will measure the same regulatory functions and roles of these molecules in human macrophages derived from circulating precursor cells obtained from subjects with varying degrees of CAD, and correlate these findings with plaque composition in humans. Finally, one of the key regulatory functions the project will assess is “efferocytosis”, the clearing of inflammatory debris by macrophages, a process recognized as a potential key determinant of halting inflammation in the plaque and a new treatment target for the future.