Excess TGFBeta in Neonatal Lung Injury and Repair

新生儿肺损伤和修复中过量的 TGFβ

• 批准号: 7827979
• 负责人: DAVID WARBURTON
• 金额: $ 31.66万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7827979
• 关键词: Alveolar; Alveolus; Borderline Personality Disorder; Bronchopulmonary Dysplasia; Candidate Disease Gene; Chronic; Endotoxins; Family; Fibrosis; Gene Targeting; Health; Human; Hyperoxia; Inflammatory; Injury; Knockout Mice; Lung; Mediating; Modeling; Molecular; Morphogenesis; Neonatal; Newborn Infant; Pathway interactions; Peripheral; Phenocopy; Phenotype; Play; Premature Birth; Process; Production; Pulmonary Emphysema; Rattus; Recombinants; Research Personnel; Risk; Rodent; Role; Signal Pathway; Signal Transduction; TNF gene; Testing; Time; Transforming Growth Factor beta; Viral Vector; base; critical period; decorin; endotoxin receptor; gene function; gene induction; injury and repair; interstitial; lung basal segment; lung injury; neonatal lung injury; novel therapeutics; outcome forecast; overexpression; premature; prevent; programs; receptor; recombinant virus; repaired

Hypothesis: Therapies aimed at negatively modulating specific targets upstream of, within or downstream of the TGF13 signaling pathway may prevent neonatal lung injury, augment neonatal lung repair and hence optimize alveolar formation. Aim 1. Candidate gene induction in the upstream cascade: to determine the impact of neonatal hyperoxia and/or LPS endotoxin on time and space-specific expression and activity of ILll3 and TNFo_, their cognate receptors, Toll family LPS endotoxin receptors and TGF13 expression and signaling in neonatal lung. Aim 2. Candidate upstream target gene function: to compare the impact of neonatal hyperoxi_ and/or LPS endotoxin, versus local overexpression of IL1-13, or TNF-_, or TGF-(_ using recombinanl viral vectors to determine which of them most closely phenocopies BPD by abrogation ol alveolarization. Aim 3. Synergy between candidate upstream target genes: to determine whether synergy tc abrogate formation of alveoli exists between neonatal hyperoxia, LPS endotoxin, ILl13, TNFo_, and/or TGF-13 in our neonatal rat model. Aim 4. Smad3 as a common downstream target mechanism: to discover whether the effects ol neonatal hyperoxia, and/or LPS endotoxin injury as well as of ILll3, TNF(_, and/or TGF13 signaling ir neonatal lung are transduced through a common TGF-odSmad3 signaling pathway, using the Smad,_ null mouse as a test model. Aim 5. Protection: to determine whether the negative sequelae of neonatal hyperoxia and/or LP5 endotoxin injury on alveolar formation can be blocked or ameliorated, either upstream or downstrearr within the TGF-13 pathway using recombinant viruses expressing Decorin or Smad7.

假设：旨在负面调节特定靶点上游、内部或 TGF-13信号通路下游可能预防新生儿肺损伤， 修复并因此优化肺泡形成。 目标1。上游级联中的候选基因诱导：确定新生儿 高氧和/或LPS内毒素对IL 113时空特异性表达和活性影响， TNF 0_、其同源受体、Toll家族LPS内毒素受体和TGF 13表达以及 新生儿肺中的信号传导。 目标二。候选上游靶基因功能：比较新生儿高氧_ 和/或LPS内毒素，与局部过表达IL 1 -13，或TNF-α，或TGF-α相比，使用重组质粒， 病毒载体，以确定它们中哪一个最接近表型BPD通过废除或 肺泡化 目标3。候选上游靶基因之间的协同作用：以确定是否协同tc 在新生儿高氧、LPS内毒素、IL 113、TNF α和/或TNF α之间存在肺泡的消除形成。 TGF-13在我们的新生大鼠模型中。 目标4。Smad 3作为一个共同的下游靶机制：发现是否影响或 新生儿高氧和/或LPS内毒素损伤以及IL 113、TNF α和/或TGF β 1 3信号转导通路的影响。 新生儿肺是通过一个共同的TGF-odSmad 3信号转导途径，使用Smad， 空小鼠作为试验模型。 目标5。保护：确定新生儿高氧和/或LP 5的阴性后遗症是否 内毒素对肺泡形成的损伤可被阻断或减轻，无论是上游还是下游 使用表达核心蛋白聚糖或Smad 7的重组病毒在TGF-13途径内进行。