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Redox-dependent signaling in hyperoxia-induced retinal vascular arrest

高氧诱导的视网膜血管骤停中的氧化还原依赖性信号传导

基本信息

批准号：
10285880
负责人：
Faizah Naheed Bhatti
金额：
$ 18.13万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10285880
关键词：
Affect Air Apoptosis Apoptotic Area Binding Biochemistry Bioinformatics Biometry Blindness Blood Vessels Cell Death Cell physiology Cells Childhood Clinical Treatment Cytoprotection Data Detection Development Disease Disulfides Endothelial Cells Endothelium Environment Enzymes Experimental Models Exposure to Genetic Genome Goals Growth Human Hyperoxia Hypoxia In Vitro Infant Inhibition of Apoptosis Injury Knowledge Lead MAP3K5 gene Mediating Modeling Modification Molecular Mus Neonatal Outcome Oxidation-Reduction Oxides Oxidoreductase Oxygen Pathogenesis Pathologic Pathology Pathway Analysis Pathway interactions Phase Postnatal Care Premature Infant Process Proteins Proteome Proteomics Research Respiratory distress Retina Retinal Diseases Retinopathy of Prematurity Risk Role Signal Pathway Signal Transduction Suggestion Sulfhydryl Compounds TXN gene TXNIP gene Testing Transgenes Transgenic Mice Vascular Endothelial Growth Factors Vascularization angiogenesis antioxidant enzyme base blood vessel development clinical care design genetic manipulation improved in vivo inhibitor/antagonist migration mouse model mutant neovascularization new therapeutic target novel therapeutics oxidation postnatal development sensor supplemental oxygen

项目摘要

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.

项目摘要早产儿视网膜病变（ROP）是由视网膜血管生长停滞，随后代偿性视网膜病变引起的。在暴露于辅助供氧治疗呼吸道疾病期间依赖性异常新生血管形成早产儿的痛苦。由于氧分压对血管停止和新生血管形成都至关重要在ROP的各个阶段，定义视网膜内皮细胞中的氧依赖性信号通路是一个关键的屏障，了解ROP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期间的信号传导包括氧分压变化的扰动（例如高氧、缺氧）。蛋白质巯基氧化是部分通过硫氧还蛋白1等专用氧化还原酶的巯基氧化还原酶活性进行调节（Trx1）和Trx1的内源性抑制剂硫氧还蛋白相互作用蛋白（Txnip）。这表明硫醇蛋白质组在高氧依赖性血管生长停滞、Trx 1和Txnip的视网膜表达期间改变在ROP和Txnip缺陷小鼠的实验模型中，凋亡标志物的表达。因此，本项目检验了Trx 1：Txnip轴作为氧化还原扰动的分子传感器，以影响ROP期间高氧诱导的视网膜血管停滞。以下具体目的是在ROP的实验小鼠模型中利用遗传和分子方法研究Trx 1和Txnip在与ROP相关的高氧依赖性血管生长停滞中的作用，确定视网膜内皮中氧依赖性信号通路：（目的1）确定Trx 1和Txnip 表达影响ROP诱导的血管骤停，（目的2）定义氧敏感性，Trx 1依赖性视网膜内皮细胞中的信号通路。该项目的成功完成将加速发现视网膜内皮细胞中的氧依赖性信号通路，了解ROP的发病机制，并促进新的治疗和临床护理方法的开发以改善ROP结果。