Role of C/EBPalpha in Cytoprotection and Recovery from Lung Injury

C/EBPα 在细胞保护和肺损伤恢复中的作用

基本信息

批准号：
8237027
负责人：
MACHIKO IKEGAMI
金额：
$ 37.13万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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：
2009-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8237027
关键词：
ADD-1 protein Acute Acute Lung Injury Adult Alveolar Alveolar Macrophages Animal Model Apoptosis Applications Grants Attenuated Biological Assay Birth CCAAT-Enhancer-Binding Protein-alpha CCAAT-Enhancer-Binding Proteins Cathepsin H Cause of Death Cell Differentiation process Cell Proliferation Regulation Cell physiology Chronic lung disease Clara cell Clinical Clinical Treatment Cytoprotection Data Development Dose Doxycycline Embryo Epithelial Epithelial Cell Proliferation Epithelial Cells Epithelium Exposure to Family Fetus Gene Expression Gene Targeting Genes Health Homeostasis Human Hyperoxia In Vitro Infant Infection Inflammation Injection of therapeutic agent Injury Intraperitoneal Injections Lung Lung Inflammation Lung diseases Mediating Messenger RNA Molecular Morbidity - disease rate Morphogenesis Morphology Mus Naphthalene Normal tissue morphology Organ Oxygen Pathway interactions Patients Pepsinogen C Peptide Hydrolases Play Pregnancy Prevention Process Processed Genes Proteins Rattus Recombinants Recovery Regulation Respiratory distress Respiratory physiology Role Signal Pathway Signal Transduction Structure of parenchyma of lung Structure of respiratory epithelium Survival Rate System Testing Therapeutic Effect Time Transgenic Mice Type II Epithelial Receptor Cell Up-Regulation alveolar type II cell bZIP Domain base cell injury cell motility effective therapy fetal improved in vivo injured keratinocyte growth factor laser capture microdissection lung injury lung maturation lung repair member migration mortality novel postnatal programs promoter protective effect repaired respiratory response surfactant trafficking tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Many of the transcriptional pathways involved in lung morphogenesis are expressed in the postnatal lung and induced during acute lung injury (ALI) to mediate repair of the lung. C/EBP( plays an important role in normal lung morphogenesis. The role(s) and mechanisms by which C/EBP( influences postnatal pulmonary homeostasis are presently unknown. Patients with ALI require high oxygen for survival and hyperoxia contributes to cellular injury that may exacerbate recovery. Our novel findings in Preliminary Data demonstrated that cre-mediated deletion of C/EBP( in respiratory epithelial cells using CCSP as promoter (Cebp(?/? mice) render the mice highly susceptible to hyperoxia, associated with decreased SP-B, severe lung inflammation, enlarged alveolar space, bronchiolar epithelial cell injury, and high mortality. Cebp( ?/? mice grow normally without any pulmonary disorder, suggesting that C/EBP( does not play a critical role in postnatal pulmonary homeostasis under normal conditions. In Cebpa?/? mice exposed to hyperoxia, mature SP-B in BALF was significantly decreased without any changes in SP-B mRNA or pro-SP-B expression, indicating that C/EBP( regulates the processing or trafficking of SP-B, a protein critical for lung function during hyperoxia. Furthermore, significantly delayed recovery of Cebp( ?/? mice after destruction of bronchiolar epithelial cells by naphthalene injection was demonstrated in our Preliminary Data. Recombinant human (rh) FGF-7 treatment showed considerable efficacy in protecting lung from hyperoxia and FGF-7 increased C/EBP( in cultured type II cells and rat lung. This grant application will determine the novel role(s) and mechanisms by which C/EBP( and its associated pathways mediate protection of the lung during alveolar and bronchiolar epithelial cell injury, and will identify the cellular processes and genes critical for repair of the lung (Aim 1). In Aim 2, we will demonstrate the critical role of regulation of C/EBP( induced by rhFGF-7 treatment during hyperoxia ALI. Understanding the precise molecular mechanisms of FGF-7 treatment for survival would help in the clinical use of rhFGF-7 for treatment of ALI. PUBLIC HEALTH RELEVANCE: Acute lung injury remains a major cause of morbidity and mortality. This proposal will determine the role and mechanisms by which C/EBPa mediates protection of the lung during acute lung injury. Furthermore, the molecular mechanisms, in particular the signaling pathways regulating Cebpa, of recombinant human FGF-7 treatment for acute lung injury will be determined.

描述（由申请人提供）：许多涉及肺形态发生的转录途径在出生后的肺中表达，并在急性肺损伤（ALI）期间被诱导以介导肺的修复。 C/EBP( 在正常肺形态发生中发挥重要作用。C/EBP( 影响出生后肺稳态的作用和机制目前尚不清楚。ALI 患者需要高氧才能生存，高氧会导致细胞损伤，从而可能导致细胞损伤。我们在初步数据中的新发现表明，在使用 CCSP 作为启动子的呼吸道上皮细胞中，cre 介导的 C/EBP( 删除 (Cebp(?/? 小鼠)) 使小鼠高度恢复。易受高氧影响，与 SP-B 减少、严重肺部炎症、肺泡腔扩大、细支气管上皮细胞损伤和高死亡率有关。 Cebp( ?/? 小鼠生长正常，没有任何肺部疾病，表明 C/EBP( 不起作用。在正常条件下对出生后肺稳态的关键作用在暴露于高氧的 Cebpa?/? 小鼠中，BALF 中的成熟 SP-B 显着减少，而 SP-B mRNA 或 pro-SP-B 表达没有任何变化。表明 C/EBP( 调节 SP-B 的加工或运输，SP-B 是一种在高氧状态下对肺功能至关重要的蛋白质。此外，我们的初步数据表明，通过注射萘破坏细支气管上皮细胞后，Cebp(?/? 小鼠的恢复显着延迟。重组人 (rh) FGF-7 治疗在保护肺免受高氧损伤方面显示出相当大的功效，并且 FGF-7 增加C/EBP( 在培养的 II 型细胞和大鼠肺中。这项拨款申请将确定 C/EBP( 及其相关途径介导肺保护期间的新作用和机制肺泡和细支气管上皮细胞损伤，并将识别对肺修复至关重要的细胞过程和基因（目标 1）。在目标 2 中，我们将证明 rhFGF-7 治疗期间诱导的 C/EBP 调节的关键作用。高氧性 ALI。了解 FGF-7 治疗生存的精确分子机制将有助于临床使用 rhFGF-7 治疗 ALI。公众健康相关性：急性肺损伤仍然是一个重要问题。发病和死亡的主要原因。该提案将确定C/EBPα在急性肺损伤期间介导肺保护的作用和机制。此外，还将确定重组人FGF-7治疗急性肺损伤的分子机制，特别是调节Cebpa的信号通路。