权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Roles of pulmonary and hepatic P4501A enzymes in hyperoxic lung injury in mice

肺和肝 P4501A 酶在小鼠高氧性肺损伤中的作用

基本信息

批准号：
7826234
负责人：
BHAGAVATULA MOORTHY
金额：
$ 2.03万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7826234
关键词：
4 hydroxynonenal Acute Adult Adult Respiratory Distress Syndrome Air Animals Biological Assay Bronchopulmonary Dysplasia CYP1A1 gene CYP1A2 gene Catalysis Cell Culture Techniques Cells Clara cell Cytochrome P450 Cytochromes DNA Development Electron Transport Electrophoretic Mobility Shift Assay Elements Enzymes Exposure to F2-Isoprostanes Foundations Functional disorder Gene Expression Genes Genetic Transcription Glutathione Guanosine Hepatic Histology Human Hyperoxia Image Immunohistochemistry In Vitro Indium Individual Infant Inflammation Inflammatory Injury Interleukins Isoprostanes Knock-out Knockout Mice Ligands Lipid Peroxidation Liquid substance Liver Luciferases Lung Lung diseases Malondialdehyde Mass Fragmentography Measures Mediating Metabolism Microsomes Molecular Mus NADP Neutrophil Infiltration Organ Oxidants Oxidative Stress Oxidoreductase Oxygen Oxygen Therapy Care Patients Play Predisposition Premature Infant Prevention Prevention strategy Production Proteins Pulmonary Edema Pulmonary Valve Insufficiency Reactive Oxygen Species Reporter Genes Research Research Personnel Respiratory distress Reverse Transcriptase Polymerase Chain Reaction Role Running Site-Directed Mutagenesis Syndrome Testing Time Transcriptional Activation Transfection Transgenic Mice Transgenic Organisms Western Blotting Wild Type Mouse adduct chromatin immunoprecipitation cytokine detoxication enzyme activity in vivo lung injury male neutrophil novel strategies overexpression oxidation promoter protein expression receptor research study response transcription factor

项目摘要

Supplemental oxygen administration is used extensively in the treatment of pulmonary insufficiency that is commonly observed in patients with acute respiratory distress syndrome (ARDS) and in preterm and term infants. However, hyperoxia causes lung damage in animals and humans. The central hypothesis of the research proposed in this application is that hyperoxia induces cytochrome P4501A (CYP1 A) enzymes in vivo through mechanisms involving transcriptional activation of the corresponding promoters, and that the induced CYP1A enzymes play protective roles against hyperoxic lung injury by catalyzing the detoxication of ROS-generated endogenous molecules (e.g., F2isoprostanes and isofurans), whose levels are elevated in the lungs of hyperoxic animals. The Specific Aims are : (1) To test the hypothesis that hyperoxia induces CYP1A1 and 1A2 gene expression through mechanisms involving transcriptional activation of the CYP1A1 or 1A2 promoter, presumably by generating endogenous ligands for the Ah receptor (AHR). We will use a transgenic mouse carrying a 10 kb human CYP1A1 promoter or a 8 Kb mouse promoter and luciferase reporter gene. These mice will be maintained in room air or exposed to hyperoxia for selected time points, and luciferase activities will be determined by in vivo bioluminescent imaging. (2) To characterize the molecular mechanisms of modulation of CYP1A1 gene by hyperoxia in cultured mouse lung cells. Mouse transformed Clara cells (mtCC) will be exposed to hyperoxia and time- dependent effects on CYP1A1 parameters'will be determined. (3) To test the hypothesis that mice lacking the gene for CYP1A1, CYP1A2,or both genes (CYP1A1/1A2 double knockouts) will be more susceptible to hyperoxia-induced lung injury than similarly exposed wild type mice, and that the CYP1A enzymes play ' protective roles against hyperoxic lung injury by catalyzing the detoxication of ROS-generated endogenous molecules (e.g., F2 isoprostanes) in the lungs of hyperoxic animals. The mice will be exposed to hyperoxia for selected time points, and parameters of lung injury and those of pulmonary and hepatic CYP1A1/1A2 expression (run-on transcription, real time RT-PCR/Northern, Western, enzyme activities) will be studied. Levels of F2 isoprostanes and isofurans will be measured in lung and liver by gas chromatography/ mass spectrometry (GC-MS). (4). To test the hypothesis that liver P450s contribute to hyperoxic lung injury in vivo. We will expose wild type, and liver- specific P450 reductase (CPR) null mice to hyperoxia, and determine if hyperoxic responses are altered in the CPR-null mice. The long-term of this proposal is to develop rational strategies for the prevention and/or treatment of chronic lung diseases in infants and adults suffering from respiratory distress and lung dysfunction.

补充供氧广泛应用于肺部疾病的治疗