Hyperoxic Modulation of Thioredoxin Signaling

硫氧还蛋白信号传导的高氧调节

基本信息

批准号：
10261027
负责人：
Peter Vitiello
金额：
$ 37.92万
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：
2017
资助国家：
美国
起止时间：
2017-08-10 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10261027
关键词：
Adverse effects Affinity Alveolar Antioxidants Atmosphere Biochemistry Bioinformatics Birth Blood Vessels Bronchopulmonary Dysplasia Cell Death Cell physiology Cessation of life Clinical Treatment Complex Computer Analysis Cysteine Cytochrome c Reductase Cytoprotection Data Development Disulfides Embryo Environment Epithelial Epithelial Cells Epithelium Functional disorder Gene Dosage Generations Genetic Glutathione Goals Growth Hyperoxia Hypoxia Impairment Injury Knowledge Label Link Lung Mitochondria Modification Molecular Morbidity - disease rate Mus Oxidants Oxidation-Reduction Oxidative Phosphorylation Oxides Oxygen Pathologic Perinatal Physiological Premature Infant Process Proteins Proteomics Regulation Research Respiratory physiology Role Signal Pathway Signal Transduction Sulfhydryl Compounds System TXN gene Therapeutic Therapeutic Effect Therapeutic Uses Thioredoxin-2 Tissues Transgenes alveolar epithelium base clinical care design enzyme activity experimental study fetal genetic manipulation in utero in vivo inducible gene expression injury and repair lung development lung injury mortality mouse model mutant novel novel diagnostics novel strategies novel therapeutic intervention overexpression oxidation oxidative damage response response to injury sensor ventilation

项目摘要

PROJECT SUMMARY Fetal transitioning from the relatively hypoxic in utero environment to an oxygen-rich perinatal atmosphere represents an oxidative burden on the developing lung. Preterm lungs are already deficient in antioxidants and are poorly equipped to deal with this oxidative transition following parturition even before considering the adverse effects of therapeutic oxygen and ventilation required to treat poor respiratory function. Sustained therapeutic oxygen may result in bronchopulmonary dysplasia (BPD), a significant morbidity and mortality in preterm infants marked by alveolar simplification and dysmorphic vascular growth. It is imperative to identify and define how oxygen-sensitive signaling pathways contribute to alveolar growth and injury in settings of altered oxygen tension. Reversible oxidation of cysteine thiols has emerged as an important signaling paradigm to modulate protein activity in response to redox perturbations. Such thiol switches are regulated by the enzyme activities of thioredoxin and glutathione superfamilies. We recently identified thioredoxin-1 (Trx1) and thioredoxin-2 (Trx2) as critical regulators of cysteine oxidation during hyperoxic injury. We hypothesize that Trx1 and Trx2 act as molecular sensors of atmospheric oxygen tension that modulate alveolar development and injury/repair responses during redox perturbations associated with developmental oxidative transitions during parturition and hyperoxic injury. However, the physiological contribution of redox signaling via thioredoxin-dependent thiol switches is unknown since genetic disruption of either Trx1 or Trx2 expression is embryonic lethal and in vivo data are exclusively generated with overexpression of transgenes. The following Aims investigate how thioredoxin regulation thiol switches influences tissue and cellular physiologies and molecular functions in response to redox perturbations caused by atmospheric oxygen tension Determine if : (1) Trx1 activity influences alveolar growth and injury during oxygen transitions, (2) Identify oxygen-sensitive Trx1- dependent signaling pathways regulated via reversible oxidation of cysteine thiols, and (3) Examine how Trx2 regulates oxygen-induced mitochondrial injury and lung epithelial cell death. Fundamental knowledge gained from this project will provide new understanding on thioredoxin-dependent thiol switches regulation of responses during redox perturbations. The overarching goal of this project is to accelerate the discovery of key thioredoxin regulatory nodes of redox-dependent signaling networks and harness this information for the development of new diagnostic and therapeutic approaches for BPD. alveolar development and injury

项目概要胎儿从相对缺氧的子宫环境过渡到富氧的围产期环境代表了发育中肺部的氧化负担。早产儿的肺部已经缺乏抗氧化剂即使在考虑之前，也没有能力应对分娩后的这种氧化转变治疗呼吸功能不良所需的治疗性氧气和通气的不良反应。持续治疗性氧气可能导致支气管肺发育不良 (BPD)，这是一种严重的发病率和死亡率早产儿的特点是肺泡简化和血管生长畸形。必须要认清并定义氧敏感信号通路如何促进肺泡生长和损伤氧张力改变。半胱氨酸硫醇的可逆氧化已成为一种重要的信号传导响应氧化还原扰动调节蛋白质活性的范例。这种硫醇开关受调节硫氧还蛋白和谷胱甘肽超家族的酶活性。我们最近鉴定了硫氧还蛋白-1 (Trx1) 和硫氧还蛋白-2 (Trx2) 作为高氧损伤期间半胱氨酸氧化的关键调节因子。我们假设 Trx1 和 Trx2 作为大气氧张力的分子传感器，调节肺泡发育以及与发育氧化转变相关的氧化还原扰动期间的损伤/修复反应分娩和高氧损伤期间。然而，氧化还原信号的生理贡献硫氧还蛋白依赖性硫醇开关尚不清楚，因为 Trx1 或 Trx2 表达的遗传破坏是胚胎致死和体内数据完全是通过转基因的过度表达产生的。下列目标调查如何硫氧还蛋白调节硫醇开关影响组织和细胞生理学响应氧化还原扰动引起的分子功能大气氧张力确定：（1） Trx1 活性影响氧转换过程中的肺泡生长和损伤，(2) 识别氧敏感的 Trx1- 通过半胱氨酸硫醇的可逆氧化调节依赖的信号通路，以及 (3) 检查 Trx2 如何调节氧诱导的线粒体损伤和肺上皮细胞死亡。获得的基础知识该项目将为硫氧还蛋白依赖性硫醇开关调节提供新的认识氧化还原扰动期间的响应。该项目的总体目标是加速发现氧化还原依赖性信号网络的关键硫氧还蛋白调节节点利用这些信息来开发 BPD 的新诊断和治疗方法。肺泡发育与损伤