Regulation of Hypoxia Inducible Factor -1a in Alveolar Epithelial Cells in Lung Contusion

肺挫伤肺泡上皮细胞缺氧诱导因子-1a的调控

• 批准号: 9249080
• 负责人: KRISHNAN RAGHAVENDRAN
• 金额: $ 30.23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249080
• 关键词: Acute; Adult Respiratory Distress Syndrome; Alveolar; Alveolar Macrophages; Apoptosis; Autopsy; Blast Cell; Blast Injuries; CASP1 gene; CCAAT-Enhancer-Binding Protein-alpha; Cell Nucleus; Cells; Chest; Contusions; Critical Care; Critical Illness; Data; Development; Dimerization; Down-Regulation; Enhancers; Epithelial Cells; Evaluation; Family; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Targeting; Generations; Genes; Goals; Heart; Human; Hypoxia; Hypoxia Inducible Factor; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Knock-out; Laboratories; Lung; Lung Inflammation; Lung Transplantation; Maintenance; Mediating; Mediator of activation protein; Messenger RNA; Molecular Profiling; Molecular Target; Motor; Mus; Oxygen; Pathogenesis; Pathologic; Pathway interactions; Pharmacology; Phospholipase A2; Phospholipids; Physiological; Proliferating; Pulmonary Surfactant-Associated Protein C; Pulmonary Surfactants; RNA; Regulation; Research; Respiratory Failure; Response Elements; Risk Factors; Role; Sampling; Secondary to; Succinates; Trauma; Trauma patient; Work; bHLH-PAS factor HLF; cytokine; deprivation; dimer; genetic signature; hypoxia inducible factor 1; innovation; laser capture microdissection; lung injury; marenostrin; metabolomics; mouse model; neutrophil; promoter; public health relevance; surfactant; surfactant production; tandem mass spectrometry; targeted treatment; transcription factor; vehicular accident; ventilator-associated pneumonia

 DESCRIPTION (provided by applicant): Lung contusion (LC) is a common injury sustained by victims of motor vehicular accidents and blast trauma. It is also an independent risk factor for the development of ALI, ARDS and Ventilator Associated Pneumonia. The most physiologically relevant consequence of LC is hypoxia. Recent work in our laboratory has indicated that HIF1a regulation especially in type II alveolar epithelial cells is responsible for the pathogenesis of lng injury and inflammation following LC. The current proposal includes three specific aims. Specific aim 1 includes characterization of HIF-1a in LC and how it regulates the fate of hypoxic cells. Additionally the role of HIF-2 a will be evaluated. Specific Aim 2 evaluates the role of HIF-1a and interaction with IL-1ß in the pathogenesis of neutrophil aggregation and activation in LC. A study of promoter determinants of IL-1ß and the role of succinate and inflammasome in activation of IL-1ß is proposed. Specific aim 3 examines the role of HIF-1a in regulation of pulmonary surfactant. Detailed qualitative and quantitative analyses of the effect of HIF1a down regulation on type II AEC on surfactant will be performed. The aim includes studies of expression and regulation of Surfactant protein C secondary to HIF activity in AEC. This new and substantively different departure from the status quo for altering the acute inflammatory response and thereby the progression of LC to ALI/ARDS opens specific targets for therapy in the care of the critically ill trauma patients.

 描述（由申请人提供）：肺挫伤（LC）是一种常见的伤害持续的受害者的机动车辆事故和爆炸创伤。它也是发生ALI、ARDS和呼吸机相关性肺炎的独立危险因素。LC的最生理相关的后果是缺氧。本实验室最近的工作表明，HIF 1a的调节，特别是在II型肺泡上皮细胞是负责的病理损伤和炎症后LC。目前的建议包括三个具体目标。具体目标1包括LC中HIF-1a的表征以及它如何调节缺氧细胞的命运。此外，还将评估HIF-2a的作用。特异性目的2评估了HIF-1 α及其与IL-1 β的相互作用在LC中性粒细胞聚集和活化发病机制中的作用。对IL-1 β启动子决定簇及琥珀酸和炎性小体在IL-1 β激活中的作用进行了研究。具体目标3检查HIF-1a在调节肺表面活性物质中的作用。将对HIF 1a下调对表面活性剂上的II型AEC的影响进行详细的定性和定量分析。目的包括研究AEC中HIF活性的次级表面活性蛋白C的表达和调节。这种新的和实质上不同的改变急性炎症反应的现状，从而LC的进展为ALI/ARDS开辟了特定的治疗目标，在危重创伤患者的护理。