The proposal involves P-selectin, a transmembrane receptor on the surface of activated platelets and endothelial cells, that binds to neutrophils, monocytes and other selected cell populations. The proposal utilizes mice that are severely deficient or altered in P-selectin, and it involves three aims. First, the phenotype of P-selectin deficient mice will be analysed in terms of platelet function in models of wound repair, inflammation, atherosclerosis and metastases. Second, the individual contribution of P- selectin in the same models will be determined using chimeric mice produced through bone marrow transplantation and lacking either platelet or endothelial P-selectin. Third, the expression of P-selectin on platelets and endothelium will be altered so that the protein is expressed on the surface in a constitutive manner instead of only on an activated cell surface. This would be accomplished by deleting the cytoplasmic domain of the adhesion receptor. The overall aim of the proposal is to understand the role of P-selectin at the level of individual physiologic functions and at the level of distribution of the protein within platelets or endothelial cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL053756-01
Application #
2231845
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1994-06-01
Project End
1999-05-31
Budget Start
1994-06-01
Budget End
1995-05-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
115524410
City
Boston
State
MA
Country
United States
Zip Code
02115
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Wang, Hong-Wei; Babic, Aleksandar M; Mitchell, Heather A et al. (2005) Elevated soluble ICAM-1 levels induce immune deficiency and increase adiposity in mice. FASEB J 19:1018-20
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Babic, Aleksandar M; Wang, Hong-Wei; Lai, Margaret J et al. (2004) ICAM-1 and beta2 integrin deficiency impairs fat oxidation and insulin metabolism during fasting. Mol Med 10:72-9
Cambien, Beatrice; Wagner, Denisa D (2004) A new role in hemostasis for the adhesion receptor P-selectin. Trends Mol Med 10:179-86
Kondo, Tatsuya; Hafezi-Moghadam, Ali; Thomas, Kennard et al. (2004) Mice lacking insulin or insulin-like growth factor 1 receptors in vascular endothelial cells maintain normal blood-brain barrier. Biochem Biophys Res Commun 317:315-20
Myers, Daniel D; Hawley, Angela E; Farris, Diana M et al. (2003) P-selectin and leukocyte microparticles are associated with venous thrombogenesis. J Vasc Surg 38:1075-89
Cambien, Beatrice; Bergmeier, Wolfgang; Saffaripour, Simin et al. (2003) Antithrombotic activity of TNF-alpha. J Clin Invest 112:1589-96
Burger, Peter C; Wagner, Denisa D (2003) Platelet P-selectin facilitates atherosclerotic lesion development. Blood 101:2661-6

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