PPAR? agonists like TZDs are promising therapeutics to treat diabetes and atherosclerosis. Major targets of PPAR? action are monocyte-derived cells. Here, we aim to define how TZDs impact blood monocytes and their downstream products-macrophages and dendritic cells (DCs)-in vivo. There are two monocyte subsets: CCR2+ [Gr-1hi] """"""""inflammatory"""""""" monocytes that are readily recruited to plaques and CCR2- [Gr-1lo] blood monocytes that are less robustly recruited to inflammation, including atherosclerotic plaques. These monocyte subsets are remarkably similar between mouse and humans. Gene expression patterns of Gr- 1hiCCR2+ versus Gr-1loCCR2- blood monocytes, analyzed herein by gene array, reveal that FABP4/aP2, PPAR?, and other genes involved in regulation of lipid metabolism and regulation of atherosclerosis are highly expressed in Gr-1loCCR2- blood monocytes, in contrast to """"""""classical"""""""" Gr-1hiCCR2+ monocytes. Our preliminary data lead us to hypothesize that TZDs can prompt Gr-1hiCCR2+ monocytes to convert to Gr- 1loCCR2- monocytes; by prompting subset conversion, TZDs may reduce 'availability' of circulating CCR2+ monocytes for recruitment into plaques. The gene expression profiles suggest that Gr-1lo monocytes possess a more DC-like character and that they may be primary targets for the action of TZDs in vivo. Thus, we will test the role of the PPAR? gene and endogenous pathways that would affect its activation in maintaining the pool of Gr-1loCCR2- monocytes and determine how TZD alter this pool. We will also trace the migratory fate of both monocyte subsets to define how TZDs affect their recruitment to plaques, differentiation patterns within plaques, and potential to emigrate out of plaques, likely in the form of DC-like cells. Finally, our preliminary data indicate that DCs, at least in tissues like skin, can be mobilized to emigrate to lymph nodes by TZDs. TZD-prompted DC mobilization is particularly remarkable because the TZDs do not appear to induce maturation of the migrating DCs, as all other defined DC migration stimulants known so far. Mature DCs are thought to induce immune priming, but immature DCs are thought to be able to induce immune tolerance. Thus, our studies may be the first to uncover a pathway-initiated by activation of PPAR? in DCs-that could stimulate immature DCs to migrate and possibly induce tolerance. We will study this possibility and its relevance to artery wall DCs that accumulate in prelesional areas. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI061741-01A2
Application #
7319784
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Miller, Lara R
Project Start
2007-06-15
Project End
2012-05-31
Budget Start
2007-06-15
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$423,750
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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