The proposal is based on addressing the role of complement activation in the mechanism of tissue injury following ischemia/ reperfusion of organs. Previous evidence indicates that inhibition of C5 prevents C5a and C5b-9 induced inflammation and tissue injury in vitro and in vivo. Studies have also demonstrated that oxidative stress of endothelial cells leads to complement activation through activation of the mannose-binding lectin (MBL) pathway. Thus, the proposed studies are based on identifying the MBL ligand present in endothelial cells, which may in turn lead to novel therapies. Investigators have identified a ligand induced by oxidative stress of human endothelial cells that binds to MBL and initiates activation of complement pathway, thereby resulting in cellular activation. They have also shown that amino acid sequence of the MBL ligand mimics an acetylglucosamine, a potent inhibitor of MBL binding. The peptide (GLUPEP) inhibits complement activation following oxidative stress of endothelial cells. Screening of various known legume lectins that share a similar binding profile as MBL has lead to the discovery of lectins that bind to the same endothelial apoptosis, also bind to GLUPEP, and inhibit MBL deposition and complement activation following oxidative stress.
The specific aims are 1) to characterize the binding of lectins to hypoxic/reoxygenated endothelial cells and the isolated MBL ligand, 2) to characterize the expression of the MBL ligand following oxidative stress in HUVEC, 3) to develop and characterize small molecular weight inhibitors of the MBL ligand, and 4) to characterize the action of lectins in inhibition of ischemia/ reperfusion in vivo tissue injury response. The studies will demonstrate that specific inhibition of MBL binding will decrease complement activation and tissue injury following gastrointestinal ischemia and reperfusion.
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