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：
7626160
负责人：
MACHIKO IKEGAMI
金额：
$ 37.5万
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/7626160
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 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 Naphthalenes 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 TP53 gene 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 enhancer binding protein fetal improved in vivo injured keratinocyte growth factor laser capture microdissection lung injury lung maturation member migration mortality novel postnatal programs promoter protective effect public health relevance 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）：肺部形态发生涉及的许多转录途径在产后肺中表达，并在急性肺损伤（ALI）中诱导以介导肺修复。 c/eBP（在正常肺形态发生中起重要作用。c/eBP的作用和机制（影响出生后肺稳态目前尚不清楚。ALI患者需要高氧的生存和高氧毒性，而超氧可能会导致细胞损伤，这可能会使我们的新颖性恢复。在ere骨中的ere术，这些发现是ex的。使用CCSP作为启动子（CEBP（？/？小鼠））使高度容易受到高度氧的小鼠的上皮细胞，与SP-B减少，严重的肺部炎症，肺泡空间扩大，支气管上皮细胞损伤的肿大有关在cebpa中的稳态？在我们的初步数据中证明了通过萘注射的上皮细胞。重组人（RH）FGF-7治疗在保护肺免受高氧症中的疗效，FGF-7增加了C/EBP（在培养的II型细胞中增加了C/EBP）细支气管上皮细胞损伤，并将确定对肺修复至关重要的细胞过程和基因（AIM 1），我们将证明调节C/EBP的关键作用（由Rhfgf-7治疗在Hyperyoxia ali期间诱导的Ali中的RHFGF-7治疗。急性肺损伤仍然是发病率和死亡率的主要原因。