Awardee OrganizationMASSACHUSETTS GENERAL HOSPITAL
Description
Abstract Text
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.
Public Health Relevance Statement
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.
No Sub Projects information available for 5P01HL142494-05
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