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，长期后遗症 幸存者，没有治疗治疗。促进受损的BPD表型的分子机制 牙槽化和纤维化尚不清楚，并且这种知识差距阻碍了新的BPD的发展 疗法。 BPD主要影响肺部发育症的临床阶段出生的早产儿 （妊娠23-32周），导致高氧，炎症和机械拉伸损伤。我们的先验 工作重点是了解临时阶段伤害如何破坏发育的正常模式 途径。这些信号通路之一，Wnt，在管道阶段具有峰值激活，并逐渐 在临床阶段下降，在学期出生时很少有活性Wnt信号传导。我们最近 在患有BPD的婴儿的肺中证明了异常激活的Wnt信号传导。而且，外源 Wnt信号在我们的3D人类模型中激活Wnt信号传导，而我们的高氧小鼠模型足以再现 BPD表型在体外和Ex Vivo中，表明Wnt是BPD发病机理的重要驱动力。 转化生长因子β（TGF-β）是正常肺部必需的另一种发育途径 过多的发展导致牙槽化和纤维化受损。暴露 肺对高氧损伤导致活化的Wnt和TGF-beta信号增加，我们能够 实验性地通过单独激活Wnt诱导TGF-β信号传导。我们的初步数据表明高氧 暴露于圆锥形肺的肺导致配体Wnt5a的间充质表达增加以及 Wnt调节剂R-Spondin-3（RSPO3）的上皮表达增加，表明Wnt的空间特异性 该模型中的配体表达。因此，我们假设在肺部囊中的损伤 发育引起RSPO3的异常上皮表达和异常的间充质表达的异常表达 Wnt5a，这增加了Wnt信号传导有助于下游TGF-beta信号的激活，从而导致 BPD中发现的肺泡化和纤维化受损。我们的具体目的是：1）确定Wnt的作用 BPD中介导受损和纤维化受损的信号传导，以及2）确定机制 高氧暴露导致Wnt途径激活和TGF-β信号的上调。成功的 这些特定目标的完成将提高我们对Wnt信号对贡献的理解 发育中的肺部受伤反应，为靶向疗法提供了预防BPD的基础。其他 该提案的主要目标是制定一个集中且结构化的职业发展计划，以提供 研究人员成为一名独立医师科学家的必要培训，具有专业知识 BPD的分子机制。本提案中的实验和培训计划为 独立严格的研究计划的增长集中在发育性肺部疾病上。