Vaso-occlusion is the initiating event in sickle cell retinopathy, which occurs in 15-30 percent of African Americans (depending on genotype) with sickle cell disease. The mechanisms of vaso-occlusion are still unknown. The applicant will focus in this proposal on three possible mechanisms for vaso-occlusion in the sickle cell retina and choroid: (1) retention of dense sickle erythrocytes (RBCs) in hypoxic conditions; (2) adherence of sickle reticulocytes to vascular endothelium; and (3) the possible contribution of leukocyte (WBC) adhesion to endothelial cells. They will investigate changes in endothelial cell adhesion molecules and their counter-receptors on RBCs and WBCs, and systemic and locally produced cytokines that stimulate their up-regulation in human postmortem tissue, in transgenic mouse model of sickle cell disease, and in a rat model for human sickle RBC-mediated vaso-occlusions of retina and choroid. They will model in the rat system the elevated systemic levels of the cytokine tumor necrosis factor-alpha (TNF-alpha) which sickle cell subjects have due to organ damage from vaso-occlusions. They will also evaluate in the rat model therapeutic strategies for controlling vaso-occlusions: neutralizing antibodies against the adhesion molecules and their counter-receptors; peptides that block the interaction between adhesion molecules and their counter-receptors; and L-arginine to cause vasodilation and possibly prevent dense, irreversibly-sickled cells from being trapped in retina and choroid. This proposal will investigate the mechanisms of vaso-occlusion in sickle cell retina and choroid and suggest strategies to prevent this initiating event in sickle cell retinopathy and choroidopathy and necrosis in other organ systems.
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