This proposal is designed to define the molecular basis of sickle cell adhesion to the endothelium. Vasoocclusion is believed cause the painful, reoccurring crisis suffered by sickle cell patients. Recent evidence suggests that this vasoocclusion may be precipitated by sickle cell adhesion to the endothelium. The molecules involved on the sickle cell surface, the endothelial cell surface, and any intermediary ligands have not been clearly identified. Our working hypothesis is that sickle cells and possible normal reticulocytes contain a receptor or receptors that bind to a ligand such as unusually large von Willebrand factor (ULvWF), which in turn binds to an endothelial cell receptor(s), precipitating the vasoocclusive crises in sickle cell disease.
The specific aims of this grant are fourfold. First, we propose to identify and characterize the receptor(s) on the sickle cell surface that mediate adhesion to endothelial cells. This will involve a variety of approaches such as flow cytometry and sorting, immunoelectron microscopy, monoclonal antibody production, and adhesion assays. Second, we will identify and characterize the receptor(s) on the endothelial cell surface that mediate adhesion to sickle cells, using techniques similar to those listed above, and by testing specific receptor-deficient mutants in an endothelial-like cell line. Third, we will evaluate the role that ULvWF and other potential ligands play in the adhesion of sickle cells to endothelial cells. Finally, we will examine the contribution of activated platelets and platelet secretory products to the adhesion of sickle cells to endothelial cells. Completion of these studies should result in a greater understanding of the molecular events that contribute to the damaging, painful events in sickle cell disease and should provide a rationale for future treatment of this disease.
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