Much of the morbidity and mortality of sickle cell disease (SS-D) is caused by tissue ischemia and infarction due to vascular occlusion. Recent evidence suggests that an abnormal adherence of sickle red blood cells (RBCs) to vascular endothelium may contribute to these vaso-occlusive events. The goal of the projected research is to characterize the molecular mechanisms involved in the abnormal adherence of sickle RBCs to vascular endothelial cells. The in vitro systems used to define the RBC- endothelial cell interactions will include both static and dynamic adhesion assays using endothelial cell cultures isolated from human vascular endothelium, and RBCs, platelets and plasma isolated from patients with SS-D.
The specific aims are: 1) To identify differences in the characteristics of RBC-endothelial cell or subendothelial matrix adhesion, comparing static conditions to conditions of controlled flow, 2) To investigate the role of RBC adhesion molecule(s) and characterize the subpopulation(s) of RBCs with enhanced adhesive properties, 3) To examine the role of adhesive plasma proteins, extracellular matrix proteins and endothelial cell adhesive molecules in RBC adhesion, and 4) To study the role of platelets in RBC-endothelial cell interactions. The Iong-term goal of this research is to better understand the molecular mechanisms involved in RBC-endothelial cell interactions in the function of hemostasis, not only in SS-D, but also in normal physiology and other diseases associated with vaso-occlusive complications.
