Modulation of Neonatal Hyperoxic Lung Injury by the Aryl Hydrocarbon Receptor

芳基烃受体对新生儿高氧性肺损伤的调节

基本信息

批准号：
8579923
负责人：
Binoy Shivanna
金额：
$ 12.38万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-20 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8579923
关键词：
Activation Analysis Adult Advisory Committees Air Alveolar Apoptosis Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Attenuated Biological Assay Biometry Bronchopulmonary Dysplasia Cells Chronic lung disease Clinical Clinical Trials Cytochrome P-450 CYP1A1 Cytochrome P450 Data Development Doctor of Philosophy Educational Curriculum Electrophoretic Mobility Shift Assay Endothelial Cells Enrollment Environment Enzymes Epithelial Cells Ethics Flow Cytometry Fluorescence Funding GST-II Generations Goals Grant Human Hyperoxia In Vitro Infiltration Inflammation Isoprostanes K-Series Research Career Programs Knockout Mice Lansoprazole Lead Lung Lung Inflammation Lung diseases Mediating Medicine Mentors Messenger RNA Methods Molecular Molecular Genetics Mus NAD(P)H dehydrogenase (quinone) 1, human Necrosis Neonatal Newborn Infant Omeprazole Oxidative Stress Pathway interactions Pediatrics Phase Polyethylene Glycols Postdoctoral Fellow Predisposition Premature Birth Premature Infant Prevention Prevention strategy Proteins Proton Pump Inhibitors Reactive Oxygen Species Receptor Activation Receptor Signaling Regulation Reporting Research Research Personnel Research Training Resistance Respiratory physiology Role Scientist Signal Pathway Staining method Stains TdT-Mediated dUTP Nick End Labeling Assay Testing Time Training Training Programs Transferase Uridine Vascular Endothelial Growth Factors Vascularization Wild Type Mouse Work Writing annexin A5 career career development chemokine chromatin immunoprecipitation college cytokine improved in vivo innovation interest lung injury macrophage morphometry neonatal human novel strategies oxygen toxicity professor protective effect public health relevance

项目摘要

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.

描述（由申请人提供）：我是贝勒医学院 (BCM) 的儿科助理教授，长期以来对高氧性肺损伤有研究兴趣。我的主要职业目标是成为一名成熟的研究者，重点研究芳基碳氢化合物受体 (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，该奖重视受保护的研究时间以及高级导师参与制定教育课程并监督我的研究进展，这两者对于实现我的职业目标至关重要。作为一名博士后研究员，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。我已报名攻读 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、资助写作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 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，在确定细胞色素 P450 1A 酶在高氧性肺损伤中的机制作用以及多环芳烃对 AhR 的调节方面获得了成功的资助。除了 Moorthy 博士之外，我的顾问委员会还包括 Drs. BCM 的 Stephen Welty、Francesco DeMayo、David Moore 和 E. O'Brian Smith 是与该提案相关的研究领域的领导者。我们观察到，质子泵抑制剂奥美拉唑通过激活 AhR 减轻成年野生型小鼠的高氧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。我的研究将测试以下中心假设：质子泵抑制剂 (PPI)，即奥美拉唑和兰索拉唑，可通过激活肺 AhR 来防止新生小鼠体内高氧诱导的肺泡简化，以及体外新生人类肺细胞的氧毒性。我将通过追求以下 3 个具体目标来检验这一假设： 1. 确定 PPI 对高氧暴露的新生小鼠的肺泡化和肺血管化的影响。 2. 确定 PPI 对新生野生型 (WT) 小鼠肺 AhR 激活的影响。 3. 确定 PPI 介导的 AhR 激活对高氧暴露的人新生儿肺细胞的影响。将评估用 PPI 治疗的空气或高氧暴露的新生 WT 和 AhR-null 小鼠的肺部的 AhR 激活、肺泡化、肺血管化、氧化应激和炎症。在存在或不存在 AhR 的情况下，对暴露于空气或高氧的新生儿人肺微血管内皮和肺泡上皮细胞进行 PPI 处理，然后分析 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，这将带来预防和治疗早产儿 BPD 的新策略。