SUMMARY Chronic social stress is an integral part of our busy contemporary lives. Abundant data show that severe chronic psychosocial stress is a risk factor for cardiovascular disease and a predictor of myocardial infarction and stroke. The mechanisms by which stress contributes to the higher cardiovascular event rates are primarily attributed to secondary effects on behavior, including smoking or food intake. How stress' effect on the brain can directly impact cardiovascular disease is uncharted territory. Preclinical preliminary data from this Program's investigators describe a direct causal link between social stress, neural signals, and atherosclerosis, the lipid-driven chronic inflammatory disease that is the underlying cause of myocardial infarction and stroke. The key connecting component is the macrophage, a large phagocytic leukocyte that originates in the bone marrow and accumulates in atherosclerotic lesions. Informed by abundant published and unpublished data, we hypothesize that chronic variable stress aggravates cardiovascular disease by interfering with macrophage dynamics. Specifically, we wish to (i) understand how stress biologically affects macrophage dynamics in atherosclerosis; (ii) develop technology that monitors macrophage dynamics non-invasively; and (iii) elucidate the mechanism by which post-traumatic stress disorder (PTSD) leads to atherosclerosis. Our highly innovative Program Project comprises a diverse team of investigators with complementary expertise in cardiovascular immunology (Swirski, Fisher, Moore); preclinical cardiovascular imaging (Mulder, Nahrendorf, Calcagno); translational imaging (Fayad, Tawakol, Mani, Fuster); and neuroscience (Murrough, Shin, Pitman, Charney). Structurally, we have 3 main Projects complemented by an Administrative/Statistical Core and Imaging Core. We will tackle the Program Project's central hypothesis in three Specific Aims from the vantage points of biology, technology, and medicine. In Aim 1 (Biology) we will investigate how stress controls macrophage dynamics in mouse models of atherosclerosis. In Aim 2 (Technology), we will develop and translate non- invasive imaging approaches and nanotechnologies that monitor macrophage dynamics in atherosclerosis during stress. In Aim 3 (Medicine), we will elucidate the mechanism by which PTSD leads to atherosclerosis. Our Program Project's overarching and long-term goal is to collectively institute a sound scientific foundation for the biomedical and clinical community as how the link between stress and cardiovascular disease can be best approached and integrated in patient care.