The focus of this study is to evaluate the biological and pathological effects of P-selectin, an adhesion molecule that mediates leukocyte binding to activated endothelial cells (EC) and platelets, and therefore, an important mediator in inflammation. P-selectin is normally stored in the alpha-granules of platelets and the Weibel-Palade bodies of EC. However, the cell surface expression of P-selectin is transient: it is rapidly induced and rapidly internalized. To study the importance of the transient nature of P-selectin expression, and to better define the role of P-selectin in normal physiology as well as in disease, a mouse constitutively expressing (and therefore, overexpressing) P-selectin on the surface of platelets and EC will be constructed by homologous recombination which replaces the wild type P-selectin gene with a mutant form lacking the cytoplasmic domain (where the signals for sorting into the secretory granules are located). The resulting mice will be used to characterize the effect of P-selectin on (1) counts and clearance of platelets and neutrophils in circulation, (2) leukocyte rolling observed with intravital microscopy, (3) spontaneous inflammation observed by histological staining and leukocyte recruitment into the peritoneum after injection of inflammatory stimuli, and (4) incidence of spontaneous as well as high fat diet-induced atherosclerotic lesions by sectioning and staining of the aorta (since monocyte adhesion to endothelium may be a prerequisite in atherosclerotic plaque formation). Characterization of the phenotypes of mice that over-express P-selectin will provide not only insight into regulation of inflammatory responses, but also basis for development of new means of treatment and prevention of inflammatory diseases.
| Pesek, C A; Cooley, R; Narkiewicz, K et al. (1999) Theophylline therapy for near-fatal Cheyne-Stokes respiration. A case report. Ann Intern Med 130:427-30 |
| Hartwell, D W; Butterfield, C E; Frenette, P S et al. (1998) Angiogenesis in P- and E-selectin-deficient mice. Microcirculation 5:173-8 |
