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：
8866299
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 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8866299
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 Health 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

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，对高氧肺损伤具有长期的研究兴趣。我的主要职业目标是成为一名成熟的研究者，重点是了解芳基烃受体（AHR）在高氧引起的发育性肺损伤中的作用。我的K08提案的主要目的是获得职业发展奖，该奖项重视受保护时间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步，这对于实现我的职业目标至关重要。作为博士后研究员，我研究了成年小鼠中高氧肺损伤的分子机制，并为拟议的研究奠定了基础。我已经参加了BCM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，赠款写作和道德规范的教育和培训，以增强我的职业发展。著名的BCM为导师提供了出色的核心和丰富的环境，以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理作用方面成功提供了资金，并通过多环状芳族氢碳纤维对AHR进行调节。除Moorthy博士外，我的咨询委员会还包括Drs。 Stephen Welty，Francesco DeMayo，David Moore和BCM的E. O'Brian Smith是与该提议有关的研究领导者。我们观察到，奥美拉唑是一种质子泵抑制剂，可通过激活AHR激活成人野生型小鼠的成年野生型小鼠中的高氧肺损伤和成年人类肺部细胞中的氧毒性。 AHR激活是否在新生小鼠和新生儿人肺细胞中产生相似的作用。我的研究将检验中心假设：质子泵抑制剂（PPI）（即奥丙唑和兰索拉唑）可以预防新生小鼠在体内和免受新生儿人肺细胞中的氧气毒性的肺部肺细胞的氧气毒性，可通过激活肺AHR的活化。我将通过追求以下3个特定目的来检验这一假设：1。确定PPI对暴露高氧新生小鼠肺泡化和肺血管化的影响。 2。确定PPI对新生儿野生型（WT）小鼠肺AHR激活的影响。 3。确定PPI介导的AHR激活对暴露于人类新生儿肺部细胞的高氧。将评估用PPI治疗的空气或高氧新生WT和AHR无效小鼠的肺，以评估AHR激活，肺泡，肺血管化，氧化应激和炎症。将在存在或不存在AHR的情况下用PPI处理的空气或高氧暴露的新生儿人肺微血管内皮和肺泡上皮细胞，以分析AHR激活，氧化应激，炎症，凋亡，凋亡和坏死。我预计结果将支持我的假设，这将导致预防和治疗BPD早产婴儿的新策略。