Thioredoxin Signaling and Pulmonary Development during Perina......

围产期硫氧还蛋白信号传导和肺部发育......

基本信息

批准号：
8917985
负责人：
Peter Vitiello
金额：
$ 29.75万
依托单位：
SANFORD RESEARCH/USD
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8917985
关键词：
Affect Alveolar Alveolus Animals Antioxidants Biochemical Biological Markers Birth Blood Vessels Bronchopulmonary Dysplasia Cell Death Cessation of life Child health care Data Development Disadvantaged Disease Disulfides Environment Epithelial Epithelial Cell Proliferation Epithelial Cells Genetic Glutathione Goals Growth Growth and Development function Homeostasis Hybrids Hyperoxia Hypoxia Infant Injury Instruction Lead Life Lung Lung diseases Mechanical ventilation Modification Molecular Molecular Genetics Neonatal Newborn Infant Nuclear Outcome Oxidation-Reduction Oxidative Stress Oxidoreductase Oxygen Oxygen measurement, partial pressure, arterial Partial Pressure Pathology Pathway interactions Pediatric Research Play Predisposition Premature Infant Protein Biochemistry Proteins Proteome Proteomics Pulmonary Hypertension Respiratory Tract Infections Respiratory physiology Role Signal Pathway Signal Transduction Site Sulfhydryl Compounds Supplementation Surface Syndrome Testing Therapeutic Intervention Thioredoxin Uterus Yeasts antioxidant enzyme asthmatic base coping design dithiol glutaredoxin improved in utero in vivo innovation insight lung maturation mouse model new therapeutic target novel therapeutics peroxiredoxin postnatal respiratory

项目摘要

PROJECT SUMMARY (See instructions): The transition from an in utero environment to life outside the womb is marked by a change from a relatively hypoxic environment (<3% oxygen) to a more oxidative atmospheric environment (21% oxygen). Lungs of prematurely born infants are underdeveloped with fewer alveoli and relatively lower expression of antioxidant enzymes. Consequently, premature infants are at a disadvantage in coping with this oxidative transition, even before therapeutic interventions such as supplemental oxygen (hyperoxia) and mechanical ventilation are considered. Bronchopulmonary dysplasia (BPD) is one possible result of sustained oxygen supplementation in premature infants, which is marked by alveolar simplification, pulmonary hypertension, and dysmorphic vascular growth. BPD adversely affects long-term lung function as evidenced by enhanced susceptibility to respiratory infection and development of an asthmatic-type syndrome. Thus, there is an urgent need to understand how oxygen tension regulates alveolar epithelial development and how environmental alterations result in newborn disease pathologies. Thiol modifications have been shown to play a major role in redox signaling pathways by regulating protein activity and are known to contribute to pulmonary disease pathologies. Thioredoxin-1 (Trxl) is a redox-sensitive protein containing a dithioldisulfide site responsible for oxidoreductase activity, making it a unique regulator of redox homeostasis since it can directly transcribe changes in oxygen tension (such as during birth or newborn oxidative injury) into developmental pathways by modifying thiol redox status. Therefore, we will test the hypothesis that newborn oxygen alters alveolar growth and development via Trx1. Goals of the proposed studies are to: 1) investigate redox proteomics of the nuclear compartment during hyperoxic injury; 2) examine how Trx1 regulates alveolar development during neonatal hyperoxia; and, 3) identify Trx1-dependent redox-sensitive signaling pathways altered during hyperoxic treatment. By identifying cellular mechanisms underlying redoxdependent changes in pulmonary epithelial growth, we will develop innovate strategies designed to improve children's health.

项目摘要（参见说明）：从子宫内环境到子宫外生活的转变的标志是从相对缺氧的环境（<3%氧气）到氧化性更强的大气环境（21%氧气）的变化。早产儿的肺部发育不全，肺泡较少，抗氧化酶的表达相对较低。因此，即使在考虑补充氧气（高氧）和机械通气等治疗干预措施之前，早产儿在应对这种氧化转变方面也处于不利地位。支气管肺发育不良 (BPD) 是早产儿持续吸氧的可能结果之一，其特点是肺泡简化、肺动脉高压和畸形血管生长。 BPD 对长期肺功能产生不利影响，表现为呼吸道感染的易感性增加和哮喘型综合征的发生。因此，迫切需要了解氧张力如何调节肺泡上皮发育以及环境改变如何导致新生儿疾病病理。硫醇修饰已被证明通过调节蛋白质活性在氧化还原信号通路中发挥重要作用，并且已知会导致肺部疾病病理。硫氧还蛋白-1 (Trxl) 是一种氧化还原敏感蛋白，含有负责氧化还原酶活性的二硫硫键位点，使其成为氧化还原稳态的独特调节剂，因为它可以直接将氧张力的变化（例如出生或新生儿氧化损伤期间）转录为发育过程中的氧张力变化。通过改变硫醇氧化还原状态的途径。因此，我们将检验新生儿氧气通过 Trx1 改变肺泡生长和发育的假设。拟议研究的目标是：1）研究高氧损伤期间核区室的氧化还原蛋白质组学； 2）研究Trx1如何调节新生儿高氧期间的肺泡发育； 3) 识别高氧治疗期间改变的 Trx1 依赖性氧化还原敏感信号通路。通过识别肺上皮生长中氧化还原依赖性变化的细胞机制，我们将开发旨在改善儿童健康的创新策略。