Role of TGFbeta superfamily in Broncopulmonary Dysplasia

TGFbeta超家族在支气管肺发育不良中的作用

• 批准号: 8853332
• 负责人: Simon James Conway
• 金额: $ 38.42万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-24 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853332
• 关键词: Acute; Adult; Affect; Alveolar; Biological Markers; Birth; Bronchopulmonary Dysplasia; Cell Proliferation; Conflict (Psychology); Cre-LoxP; Data; Deposition; Development; Disease; Down-Regulation; Doxycycline; Dysplasia; Epithelium; Evaluation; Extracellular Matrix; Fibrosis; Follistatin; Future; Generations; Genes; Genetic; Genetic Models; Health; Hyperoxia; IL6 gene; Infant; Inflammation; Injury; Interleukin-6; Knock-out; Knockout Mice; Life; Ligands; Lung; Mediator of activation protein; Modeling; Molecular; Mus; Myofibroblast; Newborn Infant; Participant; Pathogenesis; Pathway interactions; Patients; Phase; Phenocopy; Phenotype; Physiological; Prevention; Proteins; Pulmonary Surfactant-Associated Protein C; Regulation; Role; Signal Pathway; Signal Transduction; Staging; Structure; Testing; Transducers; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Model; Up-Regulation; alveolar epithelium; clinically relevant; critical period; cytokine; genetic analysis; human disease; improved; lung development; lung injury; mouse model; novel; overexpression; physiologic model; postnatal; premature; promoter; response; therapeutic target; translational approach

DESCRIPTION (provided by applicant): Bronchopulmonary Dysplasia (BPD) continues to affect the majority of infants born extremely premature and is primarily a disease of arrested alveolarization resulting from injury to the developing saccular lung. Protective strategies have been ineffective in reducing BPD, underscoring the need to better understand the underlying pathogenesis to enable development of novel therapies. Transforming Growth Factor-� superfamily signaling regulates ECM deposition, which is critical to normal lung development, and is dynamically regulated during the saccular stage of lung development. Utilizing a clinically-relevant murine model of BPD that limits hyperoxic lung injury to the saccular stage (day 0-4 in mice) to persistently simplify adult alveolar structure, we determined TGF-�2 (but not TGF-� 1 or 3 ligands) is uniquely suppressed by O2 by day 4. Although excessive TGF-� has been implicated in BPD pathogenesis, it is often following prolonged O2 exposure coincident with late-onset fibrosis (when BPD phenotype is already well-established); it is unclear if ligand-specific TGF-� signaling within the acute phase of arrested saccular development contributes to BPD pathogenesis. In addition to TGF-�2, we show during saccular lung development that hyperoxia down-regulates the complete mechanistic pathway of TGF-� signaling, including intracellular TGF-� signal transducer, pSmad3 (which predominates in lung), as well as a novel TGF-� downstream ECM effector, �igH3. Similar to hyperoxia, genetic knockout of �igH3 impairs saccular lung development. Through targeted genetic analysis of TGF-� signaling pathways in both our physiologic (hyperoxia) and novel genetic (�igH3 null) mouse models of arrested saccular development, we identified known and novel biomarkers of BPD pathogenesis: Follistatin and Msx2 (negatively regulates myofibroblast differentiation), Cdkn1a (negatively regulates cell proliferation), and IL6 (important modulator of inflammation). We hypothesize that acute, short-lived suppression of TGF-� signaling within the saccular stage is sufficient to cause BPD, and that Tgf-�2 downregulation is the key ligand responsible and acts via suppression of Smad3 activation resulting in down-regulation of the ECM-modulating protein, �igH3. By comparing our physiologic and genetic models of BPD, we will determine whether TGF-� mis-regulation is an active participant in the mechanism of arrested alveolarization or merely a compensatory response to lung injury. Aim 1 will examine whether early phase BPD is characterized by suppressed TGF-� signaling while subsequent upregulation following prolonged hyperoxia is a compensatory response to 2nd reparative mechanisms. Aim 2 will test whether TGF-� suppression via specific loss of TGF-�2 ligand alone is able to phenocopy BPD. Aim 3 will determine the mechanism(s) by which absence of the downstream TGF-�2 effector ECM protein, �igH3, is sufficient to cause BPD.

描述（由应用提供）：支气管肺发育不良（BPD）继续影响大多数出生的婴儿极早的婴儿，并且主要是一种因受伤而导致肺泡肺部受伤的肺泡化疾病。保护策略在减少BPD方面无效，强调了更好地了解潜在的发病机理以使新疗法发展的必要性。转化生长因子 - 超家族信号传导调节ECM沉积，这对于正常的肺发育至关重要，并且在肺发育的固定阶段受到动态调节。利用临床上与临床相关的BPD鼠模型，该模型将高氧性肺损伤限制为临床阶段（小鼠的第0-4天）持续简化成人肺泡结构，我们确定了TGF-.2（而不是TGF-�1或3个浓度，但在第4天都被O2均独特地抑制了IS。 O2与晚期纤维化的暴露相吻合（当BPD表型已经建立良好时）；目前尚不清楚在被捕的糖果发育的急性阶段内配体特异性TGF-信号是否有助于BPD发病机理。除TGF-�2外，我们还显示了在牙周肺发育期间，高氧降低了TGF- signaling的完整机械途径，包括细胞内TGF- signal signal dendducer，PSMAD3（PSMAD3）（在肺中占主导地位），以及一种新型的TGF-tgf-ecm ecm ecm ecm ecm ecm ecm ecm效应。与高氧相似，IGH3的遗传敲除损害了肺肺发育。通过在我们的生理（高氧）和新颖的遗传（IGH3 NULL）小鼠模型中对TGF-信号途径进行的针对性遗传分析，我们确定了BPD发病机理的新型生物标志物：follistatin和MSX2（负调节肌纤维分化），cdkn1a（负调节CDKN1A）（负调节）（负调节）（负调节）。炎症）。我们假设在晶状体阶段内急性，短暂的TGF-信号抑制足以引起BPD，而TGF-�2下调是负责的关键配体，并且通过抑制Smad3激活而导致ECM调节蛋白下调的抑制作用。通过比较我们的BPD的生理和遗传模型，我们将确定TGF-的正调是否是被阻塞肺泡化机制的积极参与者，还是仅对肺损伤的补偿性反应。 AIM 1将检查早期BPD是否以抑制TGF-信号传导为特征，而延长后随后的上调。高氧是对第二修复机制的补偿性反应。 AIM 2将测试仅通过特异性损失TGF-�2配体抑制TGF-r抑制是否能够表现BPD。 AIM 3将确定缺乏下游TGF-�2效应ECM蛋白IGH3的机制，足以引起BPD。