Modulation of Neonatal Hyperoxic Lung Injury by the Aryl Hydrocarbon Receptor

描述（由申请人提供）：我是贝勒医学院（Baylor College of Medicine）的儿科助理教授，对高氧肺损伤有着长期的研究兴趣。我的主要职业目标是成为一名成熟的研究者，专注于了解芳香烃受体（AhR）在高氧诱导的发育性肺损伤中的作用。我的K08提案的主要目标是获得职业发展奖，该奖项重视受保护的研究时间和高级导师的参与，以制定教育课程并监督我的研究进展，这两者对实现我的职业目标至关重要。作为博士后研究员，我研究了成年小鼠高氧肺损伤的分子机制，并为拟议的研究奠定了基础。我已经报名参加了由临床科学家培训计划提供的博士学位，在那里我将接受分子方法，分子遗传学，生物统计学，赠款写作和研究伦理方面的教育和培训，以提高我的职业发展。著名的剑桥大学提供了优秀的导师核心和丰富的环境来支持我的培训和研究。我的主要导师Bhagavatula Moorthy博士是一位著名的研究人员，他成功地资助了细胞色素P450 1A酶在高氧肺损伤中的机制作用，以及多环芳烃对AhR的调节。除了Moorthy博士，我的顾问委员会还包括Stephen Welty博士、Francesco DeMayo博士、大卫摩尔博士和E. O'Brian Smith是与这项提议相关的研究的领导者。我们观察到，奥美拉唑，质子泵抑制剂，减弱高氧肺损伤的成年野生型小鼠和成人肺细胞的氧毒性，通过激活的AhR。AhR激活是否在新生小鼠和新生人类肺细胞中产生类似的效果尚不清楚。我的研究将检验质子泵抑制剂（PPI）（即奥美拉唑和兰索拉唑）通过激活肺AhR在体内保护新生小鼠免受高氧诱导的肺泡简化，在体外保护新生人肺细胞免受氧毒性的中心假设。我将通过追求以下3个具体目标来测试这个假设：1。确定PPI对高氧暴露新生小鼠肺泡形成和肺血管化的影响。2.确定PPI对新生野生型（WT）小鼠肺AhR活化的影响。3.确定PPI介导的AhR活化对高氧暴露的人新生儿肺细胞的影响。将评估接受PPI治疗的暴露于空气或高氧的新生WT和AhR缺失小鼠的肺部的AhR活化、肺泡化、肺血管化、氧化应激和炎症。将分析在存在或不存在AhR的情况下接受PPI处理的暴露于空气或高氧的新生儿人肺微血管内皮细胞和肺泡上皮细胞的AhR活化、氧化应激、炎症、细胞凋亡和坏死。我预计，结果将支持我的假设，这将导致新的战略，在预防和治疗早产儿BPD。

DESCRIPTION (provided by applicant): I am an Assistant Professor in Pediatrics at Baylor College of Medicine (BCM) with a long-standing research interest in hyperoxic lung injury. My main career goal is to become an established investigator with a focus on understanding the role of aryl hydrocarbon receptor (AhR) in hyperoxia-induced developmental lung injury. The primary objective of my K08 proposal is to obtain the career development award that values protected research time and the involvement of senior mentors to formulate an educational curriculum and oversee my research progress, both of which are crucial in attaining my career goals. As a postdoctoral fellow, I investigated the molecular mechanisms of hyperoxic lung injury in adult mice and laid the groundwork for the proposed research. I have enrolled for a PhD offered by Clinical Scientist Training Program at BCM, where I will be educated and trained in molecular methods, molecular genetics, biostatistics, grant writing, and ethics in research to enhance my career development. The renowned BCM provides an outstanding core of mentors and an enriched environment to support my training and research. My primary mentor, Dr. Bhagavatula Moorthy, is a renowned researcher with successful funding in determining the mechanistic roles of cytochrome P450 1A enzymes in hyperoxic lung injury, and the regulation of AhR by the polycyclic aromatic hydrocarbons. In addition to Dr. Moorthy, my advisory committee consists of Drs. Stephen Welty, Francesco DeMayo, David Moore, and E. O'Brian Smith of BCM who are leaders in research related to this proposal. We observed that omeprazole, a proton pump inhibitor, attenuates hyperoxic lung injury in adult wild type mice and oxygen toxicity in adult human lung cells via activation of the AhR. Whether AhR activation results in a similar effect in newborn mice and in newborn human lung cells are unknown. My research will test the central hypotheses that the proton pump inhibitors (PPIs), i.e. omeprazole and lansoprazole, protect against hyperoxia-induced alveolar simplification in newborn mice in vivo and against oxygen toxicity in neonatal human lung cells in vitro via activation of the pulmonary AhR. I will test this hypothesis by pursuing the following 3 specific aims: 1. Determine the effects of the PPIs on alveolarization and pulmonary vascularization in hyperoxia-exposed newborn mice. 2. Determine the effects of the PPIs on the activation of pulmonary AhR in newborn wild type (WT) mice. 3. Determine the effects of PPI-mediated activation of the AhR on hyperoxia exposed human neonatal lung cells. The lungs of the air- or hyperoxia-exposed newborn WT and AhR-null mice treated with PPIs will be assessed for AhR activation, alveolarization, pulmonary vascularization, oxidative stress and inflammation. Air- or hyperoxia- exposed neonatal human pulmonary microvascular endothelial and alveolar epithelial cells treated with PPIs in the presence or absence of the AhR will be analyzed for AhR activation, oxidative stress, inflammation, apoptosis and necrosis. I anticipate that the results will support my hypotheses, which will lead to novel strategies in the prevention and treatment of BPD in premature infants.