Atherosclerosis is a complex chronic disease and a leading cause of myocardial infarction and stroke. At present, the dominant conceptual approaches to therapy for atherosclerosis involve manipulation of lipid metabolism and manipulation of inflammatory processes. Despite numerous efforts, mortality rates for complications of atherosclerosis continue to rise. Monocytes and macrophages are widely regarded as key cellular protagonists of atherosclerosis;not only do they promote disease through release of inflammatory mediators, but also, as lipid-rich foam cells, they become part of the disease's physical bulk. Although their indiscriminate targeting would interfere with normal homeostasis and immunity, and is therefore therapeutically nonviable, the discovery that monocytes are comprised of distinct subsets in human, mouse and other mammals suggests specialization of function, and has stimulated interest in approaches that discriminate between harmful and beneficial subsets. In this proposal we will test the hypothesis that monocyte subsets contribute differentially to atherogenesis and can be targeted selectively to image and treat the disease. Experiments will utilize classical cell biology tools, molecular profiling, and recently developed in vivo molecular imaging and therapeutic technologies that permit to interrogate monocyte biology at multiple resolutions, from the whole animal to a single cell. The project will interact closely with local imaging, immunology and cardiovascular groups and with outside collaborators. The ability to target monocyte subsets would advance our understanding of atherogenesis, and may allow us to evaluate drugs designed to selectively inhibit monocyte subset recruitment or function, and to stratify patients at risk for developing complications of atherosclerosis such as myocardial infarction or stroke.

Public Health Relevance

Atherosclerosis is a chronic disease and a leading cause of heart attack and stroke. Immune cells called monocytes are important in how the disease progresses. This grant will investigate whether it's possible to treat atherosclerosis by targeting these cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095612-04
Application #
8258729
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Olive, Michelle
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$432,312
Indirect Cost
$184,812
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Swirski, Filip K (2014) Monocyte recruitment and macrophage proliferation in atherosclerosis. Kardiol Pol 72:311-4
Kobzik, Lester; Swirski, Filip K (2014) MARCOing monocytes for elimination. Sci Transl Med 6:219fs4
Hilgendorf, Ingo; Theurl, Igor; Gerhardt, Louisa M S et al. (2014) Innate response activator B cells aggravate atherosclerosis by stimulating T helper-1 adaptive immunity. Circulation 129:1677-87
Hilgendorf, Ingo; Gerhardt, Louisa M S; Tan, Timothy C et al. (2014) Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ Res 114:1611-22
Nahrendorf, Matthias; Swirski, Filip K (2014) Fluorescent leukocytes enter plaque on the microscope stage. Circ Res 114:740-1
Swirski, Filip K; Nahrendorf, Matthias (2014) Do vascular smooth muscle cells differentiate to macrophages in atherosclerotic lesions? Circ Res 115:605-6
Swirski, Filip K; Hilgendorf, Ingo; Robbins, Clinton S (2014) From proliferation to proliferation: monocyte lineage comes full circle. Semin Immunopathol 36:137-48
Weber, Georg F; Chousterman, Benjamin G; Hilgendorf, Ingo et al. (2014) Pleural innate response activator B cells protect against pneumonia via a GM-CSF-IgM axis. J Exp Med 211:1243-56
Nahrendorf, Matthias; Swirski, Filip K (2014) Regulating repair: regulatory T cells in myocardial infarction. Circ Res 115:7-9
Pittet, Mikael J; Nahrendorf, Matthias; Swirski, Filip K (2014) The journey from stem cell to macrophage. Ann N Y Acad Sci 1319:1-18

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