Wnt Signaling in Bronchopulmonary Dysplasia

支气管肺发育不良中的 Wnt 信号转导

• 批准号: 10458630
• 负责人: Jennifer MalcolmSrygley Sucre
• 金额: $ 13.94万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458630
• 关键词: 3-Dimensional; AGTR2 gene; AXIN2 gene; Affect; Alveolar; Alveolar fibrosis; Alveolus; Animals; Automobile Driving; Award; Binding; Bronchopulmonary Dysplasia; Cells; Chemosensitization; Coculture Techniques; Complication; Data; Development; Development Plans; Disease; Environmental Risk Factor; Epithelial; Epithelial Cells; Family; Fibroblasts; Foundations; Genes; Goals; Growth; Health Care Costs; Human; Hyperoxia; Impairment; In Vitro; Infant; Inflammation; Informatics; Injury; Knowledge; Ligands; Lung; Lung diseases; Mechanics; Mediating; Mediator of activation protein; Mesenchymal; Modeling; Molecular; Mus; Newborn Infant; Nuclear; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Phosphorylation; Physicians; Play; Pregnancy; Premature Birth; Premature Infant; Productivity; Publications; Pulmonary Fibrosis; Reporter; Research; Research Personnel; Risk; Role; Scientist; Second Messenger Systems; Signal Pathway; Signal Transduction; Specificity; Stretching; Structure; Structure of parenchyma of lung; Study models; Survivors; Term Birth; Testing; Training; Training Programs; Transforming Growth Factor beta; Transforming Growth Factors; Up-Regulation; WNT Signaling Pathway; Work; alveolar epithelium; beta catenin; career development; cell type; chemical genetics; curative treatments; experience; experimental study; genetic approach; high risk; human model; improved; in vitro Model; in vivo; interstitial; long-term sequelae; lung development; lung injury; mouse model; prevent; programs; promoter; respiratory; response; response to injury; single-cell RNA sequencing; targeted treatment; transcription factor

PROJECT SUMMARY Bronchopulmonary dysplasia (BPD) is a leading complication of preterm birth, with long term sequelae in survivors and no curative treatment. The molecular mechanisms that promote the BPD phenotype of impaired alveolarization and fibrosis are not known, and this knowledge gap impedes the development of new BPD therapies. BPD primarily affects preterm infants born during the vulnerable saccular stage of lung development (23-32 weeks gestation), with resulting injury from hyperoxia, inflammation, and mechanical stretch. Our prior work has focused on understanding how saccular stage injury disrupts the normal patterning of developmental pathways. One of these signaling pathways, Wnt, has peak activation in the canalicular stage and gradually decreases during the saccular stage, with little active Wnt signaling present at term birth. We recently demonstrated aberrant activated Wnt signaling in the lungs of infants with BPD. Moreover, exogenous activation of Wnt signaling in our 3D human model and our hyperoxia mouse model is sufficient to reproduce the BPD phenotype in vitro and ex vivo, suggesting that Wnt is an important driver of BPD pathogenesis. Transforming growth factor-Beta (TGF-Beta) is another developmental pathway necessary for normal lung development that in excess contributes to impaired alveolarization and fibrosis. Exposure of saccular stage lung to hyperoxia injury results in increased activated Wnt and TGF-Beta signaling, and we are able to experimentally induce TGF-Beta signaling by activation of Wnt alone. Our preliminary data show that hyperoxia exposure of saccular stage lung results in increased mesenchymal expression of ligand Wnt5A as well as increased epithelial expression of Wnt modulator r-spondin-3 (RSPO3), suggesting spatial specificity of Wnt ligand expression in this model. We therefore hypothesize that that injury during the saccular stage of lung development causes aberrant epithelial expression of RSPO3 and aberrant mesenchymal expression of Wnt5A, and this increased Wnt signaling facilitates the activation of downstream TGF-Beta signaling, resulting in impaired alveolarization and fibrosis seen in BPD. Our specific aims are to: 1) determine the role of Wnt signaling in mediating impaired alveolarization and fibrosis in BPD, and 2) to identify the mechanisms whereby hyperoxia exposure results in Wnt pathway activation and up-regulation of TGF-Beta signaling. Successful completion of these specific aims will improve our understanding of the contribution of Wnt signaling to the injury response in the developing lung and provide a foundation for targeted therapies to prevent BPD. Another major objective of this proposal is to create a focused and structured career development plan that will provide the necessary training for the researcher to become an independent physician-scientist with expertise in the molecular mechanisms of BPD. The experiments and training program in this proposal create the structure for the growth of an independent rigorous research program focused on developmental lung diseases.

项目摘要 支气管肺发育不良（BPD）是早产的主要并发症， 幸存者和没有治愈性治疗。促进BPD表型受损的分子机制 肺泡化和纤维化尚不清楚，这一知识缺口阻碍了新的BPD的发展 治疗BPD主要影响在肺发育的脆弱囊状期出生的早产儿 （妊娠23-32周），导致高氧、炎症和机械牵拉损伤。我们事先 工作集中在了解囊状期损伤如何破坏正常的发育模式， 路径。这些信号通路之一，Wnt，在小管阶段具有峰值激活，并且逐渐地， 在囊状期减少，在足月分娩时几乎没有活跃的Wnt信号传导。我们最近 在患有BPD的婴儿的肺中证实了异常激活的Wnt信号传导。此外，外源 在我们的3D人体模型和高氧小鼠模型中，Wnt信号的激活足以复制 体外和离体BPD表型，表明Wnt是BPD发病机制的重要驱动因素。 转化生长因子-β（TGF-β）是正常肺发育所必需的另一种发育途径。 过度发育导致肺泡化和纤维化受损。囊状期暴露 肺对高氧损伤导致激活的Wnt和TGF-β信号增加，我们能够 通过单独激活Wnt实验性诱导TGF-β信号传导。我们的初步数据显示高氧 囊状期肺的暴露导致配体Wnt 5A的间充质表达增加， 增加Wnt调节剂r-spondin-3（RSPO 3）的上皮表达，表明Wnt的空间特异性 该模型中的配体表达。因此，我们推测，肺囊状期的损伤 发育引起RSPO 3的异常上皮表达和RSPO 3的异常间质表达。 Wnt 5A，并且这种增加的Wnt信号传导促进下游TGF-β信号传导的激活，导致 BPD中可见肺泡化受损和纤维化。我们的具体目标是：1）确定Wnt的作用 在BPD中介导受损的肺泡化和纤维化的信号传导，和2）确定 高氧暴露导致Wnt途径活化和TGF-β信号传导的上调。成功 这些具体目标的完成将提高我们对Wnt信号转导对细胞凋亡的贡献的理解。 在发育中的肺损伤反应，并提供靶向治疗，以防止BPD的基础。另一 这项建议的主要目标是制定一个重点突出、结构合理的职业发展计划， 必要的培训，使研究人员成为一个独立的医生，科学家与专业知识， BPD的分子机制本提案中的实验和培训计划为以下方面创建了结构： 一个独立的严格的研究计划的发展，重点是发育性肺病。