Transport and information exchange are the primary functions of blood. If oxygen transport is disrupted by atherothrombotic occlusion, downstream hypoxic cells and tissues begin dying within minutes, and if left untreated, the organism may succumb to myocardial infarction (MI) or stroke. The cellular blood components, including monocytes and neutrophils, are descendants of hematopoietic stem and progenitor cells (HSPC) and are made in the bone marrow. Innate immune cells defend us against pathogens but may also attack cardiovascular tissues, giving rise to inflamed atherosclerotic plaques, organ ischemia and failing myocardium. In the era of rapid reperfusion and statin therapy, inflammation dominates the residual risk of cardiovascular disease and thus decisively contributes to the pathogenesis of contemporary MI. Because inflammation is currently not targeted by cardiovascular clinical care, this unused opportunity for immunotherapy, which shows great promise in autoimmune and oncological diseases, is likely the next frontier in treating ischemic heart disease. To address this large unmet clinical need, we propose to go to the root of inflammation: leukocyte production, i.e. hematopoiesis. There is a tight interaction of hematopoiesis, white blood count and cardiovascular death. Altered hematopoiesis changes production rates and phenotypes of innate immune cells, which may consequently protect or attack cardiovascular organs. Vice versa, hematopoiesis is influenced by cardiovascular risk factors and disease. For instance, hematopoietic tissues are exquisitely vascularized and therefore intimately connected to blood borne information. Emerging data indicate that hyperlipidemia and acute MI activate the entire hematopoietic tree, including upstream stem cells. However, despite the long- known association between leukocytosis and CVD, surprisingly little is known about the marrow in this disease setting. This knowledge gap likely arose from the traditional separation of cardiovascular and hematology disciplines. Currently, there are few truly interdisciplinary team studying hematopoiesis in CDV. The scientists that are joining force in this application will build the missing link between the involved fields, connecting leaders in hematology (Scadden), innate immunity (Swirski), ischemic heart disease (Nahrendorf), quantitative modeling of cell population dynamics (Nowak), gene editing (Joung) and hematopoiesis imaging (Lin). This unique combination of complementary expertise creates the synergy and critical mass to study the bone marrow as a driver of cardiovascular mortality, a thoroughly novel perspective. We organize the team in 4 projects and 3 cores, which jointly pursue our overall mission from two complimentary vantage points: 1. What stem cell-intrinsic pathologies, including genetic and epigenetic alterations, cause leukocytosis and inflammation in cardiovascular organs? 2. How does cardiovascular disease change hematopoiesis and the phenotype of produced leukocytes? The four projects will pursue both perspectives, focusing on the common end point of increased output of inflammatory immune cells that damage the arterial wall and the heart.

Altered hematopoiesis changes production rates and phenotypes of innate immune cells, which may consequently protect or attack cardiovascular organs. Vice versa, hematopoiesis is influenced by cardiovascular risk factors and disease. In this application, we propose to study the bone marrow as a driver of cardiovascular mortality, a thoroughly novel perspective.