Regulation of Lung Growth and Development by Thioredoxin Interacting Protein

描述(由申请者提供)：这份建议书描述了一项为期3年的培训计划，旨在发展新生儿学的独立学术生涯。特伦特·E·蒂普尔博士完成了新生儿-围产期医学方面的有组织的奖学金培训，目前是全国儿童医院围产期研究中心和新生儿科的全职教员。他对肺发育的兴趣始于儿科住院期间，当时他认识到支气管肺发育不良(BPD)与肺氧中毒之间的联系，BPD是一种早产儿慢性肺部疾病。在团契期间，蒂普尔博士的研究重点是硫氧还蛋白依赖的机制在防御小鼠高氧肺损伤中的作用。他的直接目标是学习分子和细胞生物学的理论和应用，这些理论和应用可能应用于硫氧还蛋白系统的研究。他的长期目标是整合整个动物、分子和细胞培养技术，发展有重点的独立研究硫氧还蛋白系统在肺发育中的作用。暴露在高氧(FiO2=0.85)下的新生小鼠表现出与患有BPD的人类婴儿类似的肺发育变化。这项建议验证了一种假设，即高氧通过激活MAPK抑制与年龄相关的肺硫氧还蛋白相互作用蛋白(TXNIP)表达的发育下降，并且持续的TXNIP表达直接导致BPD新生小鼠肺发育和肺生长停滞。在这项提案中，Tipple博士将检验以下假设：1)高氧诱导TXNIP表达需要激活p38 MAPK，2)出生后II型细胞特异性遗传TXNIP缺失将改善BPD新生小鼠模型的肺生长。这项工作将在刘玉森博士的主要指导下进行，刘玉森博士是MAPK信号转导方面的公认专家，也是在肺部生物学不同方面拥有专业知识的联合导师。国立儿童医院的研究所为开展拟议的研究计划提供了一个理想的环境。他的顾问委员会的指导，加上分子和细胞技术方面的课程和技术培训，将使蒂普尔博士能够提高他进行肺发育研究的能力，这些研究将为开发预防BPD的干预措施奠定基础。 公共卫生相关性：支气管肺发育不良(BPD)是早产儿的一种慢性肺部疾病，会导致肺损伤和发育不全。BPD的原因还不是很清楚。这项拨款建议中描述的研究调查了硫氧还蛋白相互作用蛋白在模拟BPD的小鼠模型中看到的异常肺发育的贡献。

DESCRIPTION (provided by applicant): This proposal describes a 3 year training program for the development of an independent academic career in Neonatology. Dr. Trent E. Tipple has completed structured fellowship training in Neonatal-Perinatal medicine and is currently a full time faculty member of the Center for Perinatal Research and the Section of Neonatology at Nationwide Children's Hospital. His interest in lung development began during pediatric residency when he appreciated the association between bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, and pulmonary oxygen toxicity. During fellowship, Dr. Tipple's investigations focused on the role of thioredoxin-dependent mechanisms in defense against hyperoxic lung injury in mice. His immediate goal is to learn theories and applications of molecular and cellular biology that may be applied to investigations of the thioredoxin system. His long-term goal is to integrate whole animal, molecular, and cell culture techniques to develop focused independent investigations of the role of the thioredoxin system in lung development. Newborn mice exposed to hyperoxia (FiO2=0.85) exhibit alterations in lung development similar to human infants with BPD. This proposal tests the hypothesis that hyperoxia inhibits the age-related developmental decrease in pulmonary thioredoxin interacting protein (Txnip) expression through MAPK activation and that sustained Txnip expression directly contributes to altered lung development and lung growth arrest seen in the newborn mouse model of BPD. In this proposal, Dr. Tipple will test the hypotheses that 1) p38 MAPK activation is required for hyperoxia-induced Txnip expression and that 2) postnatal type II cell-specific genetic Txnip deletion will improve lung growth in the newborn mouse model of BPD. This work will be conducted under the primary mentorship of Dr. Yusen Liu, a recognized expert in MAPK signaling, and co-mentors with expertise in different aspects of pulmonary biology. The Research Institute at Nationwide Children's Hospital provides an ideal setting in which to conduct the proposed research program. Guidance from his advisory committee coupled with coursework and technical training in molecular and cellular techniques will enable Dr. Tipple to advance his ability to conduct studies of lung development that will form the foundation for the development of interventions that prevent BPD. PUBLIC HEALTH RELEVANCE: Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature infants that results in injured and underdeveloped lungs. The causes of BPD are not well understood. The studies described in this grant proposal investigate the contribution of thioredoxin interacting protein to abnormal lung development seen in a mouse model that mimics BPD.