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Wnt Signaling in Bronchopulmonary Dysplasia

支气管肺发育不良中的 Wnt 信号转导

基本信息

批准号：
10671760
负责人：
Jennifer MalcolmSrygley Sucre
金额：
$ 11.24万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10671760
关键词：
3-Dimensional AGTR2 gene AXIN2 gene Affect Alveolar Alveolus Animals Automobile Driving Award Binding Bronchopulmonary Dysplasia Cells Chemicals Chemosensitization Coculture Techniques Complication Data Development Development Plans Disease Environmental Risk Factor Epithelial Cells Epithelium Family Fibroblasts Fibrosis Foundations Genes Goals Growth Health Care Costs Human Hyperoxia Impairment In Vitro Infant Inflammation Informatics Injury Knowledge Ligands Lung Lung diseases Mechanics Mediating Mediator Mesenchymal Modeling Molecular Mus Newborn Infant Nuclear Pathogenesis Pathway interactions Patients Pattern Phenotype Phosphorylation Physicians 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 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

项目摘要

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.

项目总结摘要支气管肺发育不良(BPD)是早产的主要并发症，并有长期的后遗症。幸存者和没有根治的治疗。促进BPD表型受损的分子机制肺泡化和纤维化尚不清楚，这种知识差距阻碍了新的BPD的发展。治疗。BPD主要影响在肺发育的脆弱囊状阶段出生的早产儿 (妊娠23-32周)，因高氧、炎症和机械拉伸造成的损伤。我们的前辈工作的重点是了解球囊阶段损伤如何扰乱正常的发育模式小路。其中一个信号通路，Wnt，在小管期达到激活峰值，并逐渐在球囊阶段减少，足月出生时几乎不存在活跃的Wnt信号。我们最近 BPD患儿肺组织中Wnt信号异常激活。此外，外生性在我们的3D人体模型和我们的高氧小鼠模型中Wnt信号的激活足以复制 BPD在体外和体外的表型，提示Wnt是BPD发病的重要驱动因素。转化生长因子-β是正常肺发育所必需的另一条途径过多的发育会导致肺泡化和纤维化。球囊期显露肺对高氧损伤导致活化的Wnt和转化生长因子-β信号增加，我们能够实验上通过单独激活Wnt诱导转化生长因子-β信号传导。我们的初步数据显示高氧血症暴露于囊状期肺导致配体WNT5A和WNT5A间充质表达增加 Wnt调节剂r-Respondin-3(RSPO_3)在上皮细胞中的表达增加，提示Wnt具有空间特异性配体在该模型中的表达。因此，我们假设肺球囊期的损伤发育导致RSPO_3在上皮细胞的异常表达和间质细胞的异常表达 Wnt5A，这种增加的Wnt信号促进下游的转化生长因子-β信号的激活，从而导致 BPD的肺泡化和纤维化受损。我们的具体目标是：1)确定WNT的角色在BPD中介导受损的肺泡化和纤维化的信号转导，以及2)确定其机制高氧暴露导致Wnt通路激活和转化生长因子-β信号的上调。成功这些具体目标的完成将提高我们对WNT信号对对发育中的肺的损伤反应，并为预防BPD的靶向治疗提供了基础。另一个这项提议的主要目标是创建一个有重点和结构化的职业发展计划，该计划将提供对研究人员进行必要的培训，使其成为一名独立的内科医生兼科学家，并在 BPD的分子机制。本提案中的实验和培训计划创建了以下结构一个专注于发育性肺部疾病的独立、严格的研究计划的发展。