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Regulation of Elastin Assembly during Saccular Stage Lung Development

肺囊期发育过程中弹性蛋白组装的调节

基本信息

批准号：
10205148
负责人：
JOHN BENJAMIN
金额：
$ 14.78万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-05 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205148
关键词：
Address Adult Affect Air Sacs Amniotic Fluid Amniotic Sac Aspirate substance Bronchoalveolar Lavage Fluid Bronchopulmonary Dysplasia Data Development Distal Down-Regulation Elastic Fiber Elastin Environment Epithelial Exposure to FBLN5 gene Fetal Lung Fibroblasts Future Impairment In Vitro Infant Inflammation Inflammatory Interleukin-1 Interleukin-1 alpha Interleukin-1 beta Knowledge Link Liquid substance Long-Term Effects Lung Lung diseases Mediating Mediator of activation protein Mesenchymal Modeling Morbidity - disease rate Mus Pathogenesis Pathway interactions Perinatal Phenotype Positioning Attribute Predisposition Premature Infant Production Publishing Regulation Reporter Reporting Risk Factors Role Signal Transduction Stimulus Structure Testing Therapeutic Time Transcriptional Regulation Transgenic Mice adenoviral-mediated airway epithelium antenatal cell type chromatin immunoprecipitation fetal first responder in vivo inhibitor/antagonist insight interstitial intraamniotic infection lung development mRNA Expression microbial mouse model novel overexpression postnatal period premature premature lungs prevent promoter pulmonary function respiratory response therapeutic development transcription factor

项目摘要

PROJECT SUMMARY Perinatal inflammation is an established risk factor for bronchopulmonary dysplasia (BPD), a major morbidity of prematurity characterized by abnormal saccular stage lung development. As the airway epithelium is present at the interface of the amniotic sac environment and the fetal lung, it is well positioned to respond to inflammatory stimuli in amniotic fluid. Therefore, we developed a transgenic mouse model to inducibly express the master inflammatory transcription factor NF-κB, in the airway epithelium (IKTA mice). Using this model, we showed that epithelial-derived inflammation results in profound dilation of terminal airspaces during the saccular stage, but does not alter earlier stages of lung development. Airspace dilation in saccular stage IKTA lungs was associated with reduced expression of important elastin assembly components, especially fibulin-5, by interstitial fibroblasts, leading to altered elastic fiber assembly around distal airspaces. In new preliminary data generated to identify epithelial-derived inhibitors of elastin assembly components in fibroblasts, we found that lungs of IKTA mice and tracheal aspirates (TA) from preterm infants exposed to antenatal inflammation had high levels of IL-1 (both IL- 1α and IL-1β). Neutralizing IL-1α or IL-1β restored fibulin-5 expression in fibroblasts exposed to bronchoalveolar lavage fluid (BAL) from IKTA mice or TA from preterm infants. Since IL-1 triggers intracellular signaling via NF- κB, we tested the direct impact of NF-κB on saccular stage lung fibroblasts and observed that NF-κB signaling inhibited fibulin-5 mRNA expression. Finally, by modifying our transgenic mouse model to enable survival beyond the early postnatal period, we found that inflammation-induced disruption in saccular stage elastin organization results in persistent abnormalities in lung structure. Proposed studies will test the hypothesis that during the saccular stage of lung development, epithelial-derived inflammation propagates down-stream NF-κB activation in fibroblasts through IL-1 signaling, resulting in down-regulation of fibulin-5 and other critical elastin assembly components. Disruption of elastin organization during this critical developmental window impairs lung development, leading to abnormalities in lung structure and function that persist into adulthood. Specific aims are: 1) to define the role of IL-1 signaling in regulation of elastic fiber assembly components, 2) to determine the transcriptional regulation of fibulin-5 in lung fibroblasts during development and in response to inflammation, and 3) to investigate the long-term impact of impaired saccular stage elastin assembly. Together, our studies will determine how inflammation during a critical developmental window can modulate lung structure and function, thus providing new insights into BPD pathogenesis and the long-term consequences of altered saccular stage lung development.

项目摘要围产期炎症是支气管肺发育不良（BPD）的一个既定危险因素，BPD是支气管肺发育不良的主要发病率，以肺发育不正常的囊状阶段为特征的早产。由于气道上皮细胞存在于羊膜囊环境和胎儿肺的界面，它处于良好的位置，以响应炎症反应。羊水刺激。因此，我们开发了一种转基因小鼠模型，气道上皮中的炎症转录因子NF-κB（IKTA小鼠）。使用这个模型，我们表明，上皮源性炎症导致囊状期终末气隙的深度扩张，但不会改变肺发育的早期阶段。囊状期IKTA肺的气隙扩张与由于间质成纤维细胞减少了重要的弹性蛋白装配组分，特别是fibulin-5的表达，导致改变远端空气空间周围的弹性纤维组装。在生成的新的初步数据中，成纤维细胞中弹性蛋白组装成分的上皮来源抑制剂，我们发现IKTA小鼠和暴露于产前炎症的早产儿的气管吸出物（TA）具有高水平的IL-1（IL-1和IL-2）。 1α和IL-1β）。中和IL-1α或IL-1β可恢复暴露于支气管肺泡灌洗液的成纤维细胞中fibulin-5的表达来自IKTA小鼠的灌洗液（BAL）或来自早产婴儿的TA。由于IL-1通过NF-κ B激活细胞内信号传导， NF-κB，我们检测NF-κB对囊状期肺成纤维细胞的直接影响，并观察NF-κB信号通路抑制fibulin-5 mRNA表达。最后，通过修改我们的转基因小鼠模型，在出生后早期，我们发现炎症引起囊状期弹性蛋白组织破坏导致肺部结构的持续异常。拟议的研究将检验这一假设，即在在肺发育的囊状期，上皮源性炎症向下游NF-κB活化传播在成纤维细胞中通过IL-1信号传导，导致fibulin-5和其他关键弹性蛋白组装的下调件.在这个关键的发育窗口期，弹性蛋白组织的破坏会损害肺发育，导致肺结构和功能异常，持续到成年。具体目标目的是：1）确定IL-1信号传导在调节弹性纤维组装组分中的作用，2）确定IL-1信号传导在调节弹性纤维组装组分中的作用。在发育过程中和对炎症的应答中肺成纤维细胞中纤蛋白-5的转录调节，以及 3)研究囊状期弹性蛋白组装受损的长期影响。我们的研究将确定关键发育窗口期的炎症如何调节肺结构和功能，从而为BPD发病机制和囊状期改变的长期后果提供了新的见解肺发育