Diet, exercise, stress and sleep are receiving attention as important environmental modifiers of chronic inflammatory diseases. Accumulating evidence indicates that psychosocial stress and a diet high in fat and cholesterol aggravate, whereas regular physical activity and healthy sleeping habits help to prevent atherosclerosis. We hypothesize that clinically relevant environmental inputs affect specific biological immune pathways that can be targeted to reverse the atherosclerosis disease trajectory. Hematopoiesis, the process by which monocytes and their descendant macrophages develop from multipotent progenitors, is essential to disease development and progression. Hematopoiesis adjusts to environmental stimuli, its configuration aligning with disease severity. As atherosclerosis worsens, control of cell production in the bone marrow deteriorates. Through mechanisms we do not fully understand, protective medullary niches expel hematopoietic progenitors, which then seed secondary lymphoid organs where they give rise to inflammatory cells through extramedullary hematopoiesis. At advanced stages of disease, even mature, fully-differentiated leukocytes undergo limited hematopoiesis in the vessel wall. Here, we will test the hypothesis that real-life modifiers of disease, such as diet, exercise, stress and sleep, influence the leukocyte supply chain. We will test, using mouse models, how lifestyle changes hematopoiesis' molecular and cellular machinery during atherosclerosis. We propose that negative modification (high fat diet, lack of exercise, chronic stress, and sleep deprivation) rearranges hematopoietic geography, diverting production from the bone marrow to the periphery, thus propagating a quantitative and qualitative drift of the macrophage supply chain. We will examine the microenvironment that governs macrophage production, including growth factors, cytokines and adhesion molecules that regulate hematopoiesis (proliferation, retention, migration patterns of progenitors from bone marrow to spleen). Apoe-/- and Ldlr-/- mice will be exposed to various lifestyle changes and microenvironmental factors will be studied using double knock out mice and functional genomics approaches which rely on nanoparticle-enabled in vivo RNAi. We will further study how lifestyle alters cell-intrinsic factors that influence proliferation, migraton and phenotype of macrophages and their progenitors. Specifically, we will target transcription factors which give rise to myeloid biased hematopoietic stem cells. Our motivation is to understand how lifestyle transforms hematopoiesis and how these transformations influence the course of disease. In conjunction with improvements in public health policy, future therapeutics may involve nudging the hematopoietic tree towards reversal of risk. The work will substantially improve understanding of how leukocytes are (over)supplied in the setting of cardiovascular disease. These new insights into how the hematopoietic system is perturbed after exposure to real-life risk factors will provide a foundation for new therapeutic strategies aiming at reduction of inflammation in blood vessels, in the heart and in the brain.

Public Health Relevance

While we know that leukocytosis correlates with cardiovascular mortality, it is largely unknown how inflammatory leukocyte production is regulated in atherosclerosis. We will study how the hematopoietic system, plaque macrophage supply and phenotype is perturbed as a function of real-life lifestyle factors such as stress, diet sleep and exercise.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128264-03
Application #
9281049
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Klauzinska, Malgorzata
Project Start
2015-09-01
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
3
Fiscal Year
2017
Total Cost
$851,857
Indirect Cost
$360,960
Name
Massachusetts General Hospital
Department
Type
Independent Hospitals
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
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