Modulation of Neonatal Hyperoxic Lung Injury by the Aryl Hydrocarbon Receptor

简介(申请人提供)：我是贝勒医学院儿科学助理教授，长期从事高氧性肺损伤的研究。我的主要职业目标是成为一名知名的研究人员，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，以及资深导师的参与，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都至关重要。作为博士后，我研究了成年小鼠高氧性肺损伤的分子机制，并为拟议的研究奠定了基础。我已经注册了BCM临床科学家培训项目提供的博士学位，在那里我将接受分子方法、分子遗传学、生物统计学、拨款撰写和研究伦理方面的教育和培训，以促进我的职业发展。著名的BCM为我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酶在高氧性肺损伤中的机制作用，以及多环芳烃对AhR的调节。除了穆尔西博士，我的顾问委员会还包括BCM的斯蒂芬·韦尔蒂博士、弗朗西斯科·德梅奥博士、大卫·摩尔博士和E·奥布赖恩·史密斯博士，他们都是与这项提议相关的研究的领导者。我们观察到，质子泵抑制剂奥美拉唑通过激活AhR来减轻成年野生型小鼠的高氧性肺损伤和成人肺细胞的氧毒性。AhR激活是否会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。我的研究将验证中心假设，即质子泵抑制剂(PPI)，即奥美拉唑和兰索拉唑，在体内保护高氧诱导的新生小鼠肺泡简化，并在体外通过激活肺AhR保护新生人类肺细胞免受氧毒性。我将通过追求以下三个具体目标来验证这一假说：1.确定PPI对高氧暴露新生小鼠肺泡化和肺血管形成的影响。2.测定PPIs对新生野生型(WT)小鼠肺组织AhR活性的影响。3.确定PPI介导的AhR激活对高氧暴露的人新生肺细胞的影响。使用PPI治疗的新生WT和AhR缺失小鼠的肺将被评估AhR激活、肺泡化、肺血管形成、氧化应激和炎症。空气或高氧暴露的新生儿人肺微血管内皮细胞和肺泡上皮细胞在有或没有AhR的情况下用PPI处理，将分析AhR的激活、氧化应激、炎症、凋亡和坏死。我预计结果将支持我的假设，这将导致在预防和治疗早产儿BPD的新策略。

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.