The applicant received his doctoral degree for work on the roles of arachidonic acid metabolism and intracellular calcium mobilization in the mechanism of stimulus-response coupling in human platelets. During the past three years, while completing subspeciality training in rheumatology, the applicant has mastered techniques for the isolation and cultivation of human endothelial cells, and has developed a new quantitative assay for the study of adhesion of leukocytes to endothelial cells. In the proposed research, the applicant will combine these techniques with a detailed study of the surface glycoproteins on endothelial cells and monocytes, and will identify specific proteins that mediate monocyte-adherence to endothelial cells. In vivo data has identified circulating monocytes as the precursor cell of subendothelial lipid-laden foam cells, but have not identified the factors responsible for the intiation and regulation of monocyte-endothelial cell interactions. The applicant will examine the roles of monocyte chemoattractants, platelets, and lipoproteins on monocyte-adherence to endothelial cells. Monocyte and endothelial cell surface proteins mediating adhesion will be identified using both biochemical (proteolysis of surfact proteins) and immunological (endothelial cell and/or monocyte antibodies) techniques. Monocytes and plasma from hyperlipidemic individuals, as well as normal volunteers maintained on high fat diets, will be examined to determine whether hypercholesterolemia influences monocyte adhesion to endothelial cells. The applicants current position at the Gladstone Foundation Laboratories provides a unique opportunity to achieve these goals. David R. Phillips, Ph.D., the applicants supervisor, is an internationally recognized authority on platelet surface glycoproteins, and Robert W. Mahley, M.D., Ph.D., the Director of the Gladstone, is a reknown leader in the field of lipoprotein structure and functions. The applicant brings to this endeavour expertise in the biology and cellular interactions of the endothelium, and an extensive background in platelet physiology and biochemistry. The proposed research should increase our knowledge of the molecular mechanisms of monocyte-endothelial cell interaction. Such knowledge may form a basis for the design of rational and novel strategies to prevent and treat atherosclerosis.
| English, Denis; Klasko, Stephen K; Sanberg, Paul R (2006) Elusive mechanisms of ""stem cell""-mediated repair of cerebral damage. Exp Neurol 199:10-5 |
| Brown, D L; Phillips, D R; Damsky, C H et al. (1989) Synthesis and expression of the fibroblast fibronectin receptor in human monocytes. J Clin Invest 84:366-70 |
| Phillips, D R; Charo, I F; Parise, L V et al. (1988) The platelet membrane glycoprotein IIb-IIIa complex. Blood 71:831-43 |
| Charo, I F; Bekeart, L S; Phillips, D R (1987) Platelet glycoprotein IIb-IIIa-like proteins mediate endothelial cell attachment to adhesive proteins and the extracellular matrix. J Biol Chem 262:9935-8 |
