Inflammation plays an essential role in vascular injury in atherosclerosis and restenosis. Adhesive interactions between vascular cells orchestrate this inflammatory response. We have focused on the leukocyte integrin Mac-1 (CD11b/CD18), identifying this adhesive receptor as a molecular determinant of neointimal thickening after arterial injury. This led us to hypothesize that """"""""outside-in"""""""" signaling by Mac-1 may initiate a gene program that promotes vascular inflammation. We have cloned a novel forkhead transcription factor (Mac-l-regulated forkhead, MFH) using differential display PCR that is down-regulated in Mac-1 clustered compared to non-clustered monocytic cells. MFH functions as a transcriptional repressor of genes known to regulate monocyte differentiation, including PU.1 and c-fms, and over-expressing MFH prevents macrophage-like differentiation in vitro. The central hypothesis of this proposal is that Mac-1 engagement orchestrates monocyte differentiation signals by regulating the expression of a novel forkhead transcription repressor, thereby modulating vascular inflammation and ultimately neointimal thickening after injury.
Our specific aims are: (1) to define the molecular mechanism of MFH's ability to modulate transcriptional activity and to characterize the nature of MFH regulation by Mac-1; (2) to determine the effect of manipulating MFH expression on monocyte differentiation in vitro and in vivo; and (3) to examine the effect of retroviral bone marrow stem cell over-expression of MFH on macrophage accumulation and neointimal thickening after arterial injury. The experiments outlined in this proposal should clarify the role of Mac-1 signaling in monocyte differentiation and its importance in vascular injury. Understanding the molecular mechanisms of monocyte differentiation will provide insights necessary to develop anti-inflammatory strategies for modulating vascular injury in atherosclerosis, restenosis, and transplant arteriopathy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073852-03
Application #
6909940
Study Section
Pathology A Study Section (PTHA)
Program Officer
Wassef, Momtaz K
Project Start
2003-07-01
Project End
2006-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$410,600
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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