Redox-dependent signaling in hyperoxia-induced retinal vascular arrest

项目总结 早产儿视网膜病变(ROP)是由视网膜血管生长停滞和代偿引起的 呼吸补充氧治疗中的依赖性异常新生血管 早产儿的窘迫。因为氧分压对血管停滞和新生血管都是至关重要的 决定视网膜内皮细胞氧依赖信号通路的ROP时相是一个关键障碍 为了解ROP的发病机制，识别新的治疗靶点，并优化 产后护理环境。蛋白质硫醇的可逆氧化促进氧化还原过程中的信号传递 扰动包括氧分压的变化(例如，高氧、低氧)。蛋白质硫醇氧化是 部分地通过硫氧还蛋白1等专门的氧化还原酶的硫醇氧化还原酶活性来调节 (Trx1)和Trx1的内源性抑制物硫氧还蛋白相互作用蛋白(TXNIP)。暗示着硫醇 高氧依赖血管生长停滞、视网膜Trx1和TXNIP表达的蛋白质组改变 在ROP和TXNIP缺陷小鼠的实验模型中，增加了血管闭塞和 凋亡标记物的表达。因此，该项目测试了Trx1：TXNIP轴作为 氧化还原扰动的分子传感器在ROP过程中影响高氧诱导的视网膜血管停滞。 在ROP的实验小鼠模型中，以下特定目的利用遗传和分子方法 探讨Trx1和TXNIP在高氧依赖性血管生长受阻中的作用 识别视网膜内皮细胞中氧依赖的信号通路：(目标1)确定Trx1和TXNIP 表达影响ROP诱导的血管停滞，并(目标2)定义氧敏感，Trx1依赖 视网膜内皮细胞中的信号通路。该项目的成功完成将加速 视网膜内皮细胞氧依赖信号通路的发现，利用信息 了解ROP的发病机制，促进新的治疗和临床护理方法的发展 以改善ROP结果。

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.