Redox-dependent signaling in hyperoxia-induced retinal vascular arrest
PROJECT SUMMARY Retinopathy of prematurity (ROP) is caused by retinal vascular growth arrest followed by compensatory dependent aberrant neovascularization during exposure to supplemental oxygen given to treat respiratory distress in preterm infants. Since oxygen tension is critical for both vascular arrest and neovascularization phases of ROP, defining oxygen-dependent signaling pathways in retinal endothelial cells is a critical barrier for understanding ROP pathogenesis, identification of novel therapeutic targets, and optimization of the postnatal care environment. Reversible oxidation of protein thiols facilitates signaling during redox perturbations including changes in oxygen tension (e.g. hyperoxia, hypoxia). Protein thiol oxidation is regulated, in part, through the thiol oxidoreductase activities of dedicated redox enzymes such as thioredoxin 1 (Trx1) and an endogenous inhibitor of Trx1, thioredoxin interacting protein (Txnip). Suggestive that the thiol proteome is altered during hyperoxic-dependent vascular growth arrest, retinal expression of Trx1 and Txnip increases in an experimental model of ROP and Txnip-deficient mice have increased vaso-obliteration and expression of apoptotic markers. Therefore, this project tests the hypothesis that the Trx1:Txnip axis serves as a molecular sensor of redox perturbations to influence hyperoxia-induced retinal vascular arrest during ROP. The following specific aims utilize genetic and molecular approaches in an experimental mouse model of ROP to investigate roles of Trx1 and Txnip in hyperoxic-dependent vascular growth arrest associated with ROP and identify oxygen-dependent signaling pathways in retinal endothelium: (Aim 1) Determine if Trx1 & Txnip expression influences ROP-induced vascular arrest, and (Aim 2) Define oxygen-sensitive, Trx1-dependent signaling pathways in retinal endothelial cells. Successful completion of this project will accelerate the discovery of oxygen-dependent signaling pathways in retinal endothelial cells, harness information for understanding ROP pathogenesis, and improve development of new therapeutic and clinical care approaches to ameliorate ROP outcomes.