Inflammation plays an essential role in vascular injury and repair in atherosclerosis and restenosis. Adhesive interactions between vascular cells orchestrate this inflammatory response. During the period of this grant, we have focused on the leukocyte integrin Mac-I (CDI lb/CD 18), identifying this adhesive receptor as a molecular determinant of neointimal thickening after experimental arterial injury. These studies have revealed novel information as to how leukocytes are recruited at sites of vascular injury and how integrins are regulated and initiate """"""""outside-in"""""""" signals, suggesting new opportunities for manipulation of integrin function in vivo. The central hypotheses of this renewal application are that the interaction of leukocyte Mac-I with platelet GP Iba mediates leukocyte recruitment after vascular injury, that Mac-I function is regulated by the urokinase receptor (uPAR), and that Mac-I clustering promotes pro-inflammatory signals that drive neointimal thickening after experimental angioplasty. The overall objective of this proposal is to define the role of Mac-I-mediated inflammation in vascular injury and repair.
Our specific aims are: (1) To define the physical and functional determinants of the interactions between Mac-I,GP Ibalpha and Mac-I -uPAR; (2) To characterize signaling events induced by clustering Mac-I that promote gene expression; and (3) To determine the effects of disrupting Mac-I-GP lba and Mac-I-uPAR on leukocyte recruitment, cellular proliferation, and neointimal thickening after carotid artery injury. Because integrin function and signaling are important components of inflammation, understanding the molecular mechanisms of vascular inflammation will provide insights necessary to develop strategies for modulating vascular repair in restenosis and other accelerated arteriopathies, including transplant vasculopathy and vein graft hyperplasia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057506-08
Application #
6756510
Study Section
Pathology A Study Section (PTHA)
Program Officer
Srinivas, Pothur R
Project Start
1997-07-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
8
Fiscal Year
2004
Total Cost
$362,970
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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