FGF-10 Expression in a Fetal Mouse Lung Model of Bronchopulmonary Dysplasia

FGF-10 在支气管肺发育不良胎鼠肺模型中的表达

• 批准号: 8631921
• 负责人: Lawrence S Prince
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631921
• 关键词: Address; Affect; Agonist; Alleles; Alveolus; Animal Model; Architecture; Biochemical; Bronchopulmonary Dysplasia; Caring; Caspase; Caspase Inhibitor; Cell model; Cells; Child; Child health care; Childhood; Clinical; Clinical Data; Complex; Complication; DNA-Protein Interaction; Data; Development; Developmental Gene; Discipline of obstetrics; Disease; Epithelial; Exposure to; Family; Fetal Lung; Gene Expression; Gene Expression Regulation; Genetic Transcription; Growth Factor; Health; Hospitalization; Immune response; Immune system; Incidence; Infant; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Knock-in Mouse; Knockout Mice; Lead; Link; Lung; Macrophage Activation; Mediating; Mesenchymal; Mesenchyme; Modeling; Molecular; Molecular Models; Morphogenesis; Mus; Neonatal; Neonatology; Pathogenesis; Patients; Predisposition; Pregnancy; Premature Birth; Premature Infant; Process; Production; Proteins; Recurrence; Regulation; Respiratory physiology; Risk; Role; Signal Transduction; Source; Sp1 Transcription Factor; Staging; Stimulus; Testing; Toll-like receptors; Transcription Repressor/Corepressor; activating transcription factor; cytokine; fetal; fibroblast growth factor 10; gain of function; improved; insight; lung development; macrophage; microbial; molecular modeling; mouse model; mutant; novel therapeutics; overexpression; premature; prevent; promoter; public health relevance; receptor expression; research study; response; transcription factor

DESCRIPTION (provided by applicant): Preterm birth remains one of the most important health problems facing obstetrics and neonatology. Among the complications of preterm delivery, bronchopulmonary dysplasia (BPD) is the most common, affecting up to 50% of preterm infants born before 28 wk gestation. The lungs of patients with BPD lack normal numbers of saccular airways and mature alveoli due to arrested development. Clinical and experimental evidence now suggest the arrested lung development in BPD is likely due to inflammation and subsequent release of inflammatory mediators. Lungs from BPD patients also have reduced levels of the key growth factor FGF-10. In fetal mice, microbial products and released inflammatory mediators inhibit FGF-10 expression by activating the transcription factor NF-?B in lung mesenchymal cells. Because of this inflammation-mediated change in developmental gene expression, saccular stage airway branching morphogenesis is inhibited, producing simplified lung architecture. Fetal lung macrophages are the primary source of the inflammatory mediators including IL-1¿ that inhibit FGF-10 expression and airway morphogenesis. However, several questions regarding this mechanism remain. First, there appears to be a developmental window of susceptibility during which inflammation can alter fetal lung morphogenesis. The lack of effect on earlier stages could be due to inability of immature lung macrophages to respond to microbial stimuli or inefficiency in releasing inflammatory mediators such as IL-1¿. As part of the inflammatory response, multi-protein inflammasome complexes process and release IL-1¿. Preliminary data suggest that expression and function of the inflammasome may be developmentally regulated. In addition to the questions surrounding maturation of macrophage response, how inflammatory mediators can disrupt normal developmental gene expression in target mesenchymal cells is unknown. Recent data show that NF-?B disrupts the normal regulation of FGF-10 promoter activity by the transcription factors Sp1 and Sp3. Interactions between the NF-?B subunit RelA and Sp3 appear to convert Sp3 into a transcriptional repressor. This proposal includes three specific aims to examine the cellular and molecular mechanisms linking inflammation and abnormal lung development. The first aim will determine which aspects of the lung macrophage innate immune response are developmentally regulated. The second aim will test if inflammasome function and caspase-mediated IL-1¿ processing is required and sufficient to inhibit lung airway morphogenesis. The third aim will further investigate the molecular mechanisms linking NF-?B and changes in FGF-10 expression. These studies will better define how inflammation affects lung morphogenesis and identify potential targets for developing novel therapeutic strategies for preventing and treating BPD in preterm infants.

描述（由申请人提供）：早产仍然是产科和妇产科面临的最重要的健康问题之一。在早产的并发症中，支气管肺发育不良（BPD）是最常见的，在妊娠28周前出生的早产儿中，影响高达50%。BPD患者的肺由于发育停滞而缺乏正常数量的囊状气道和成熟的肺泡。临床和实验证据表明，BPD患者的肺发育受阻可能是由于炎症和随后的炎症介质释放。来自BPD患者的肺也具有降低的关键生长因子FGF-10水平。 在胎鼠中，微生物产物和释放的炎症介质通过激活转录因子NF-？肺间充质细胞中的B。由于这种炎症介导的发育基因表达的变化，囊状期气道分支形态发生被抑制，产生简化的肺结构。胎肺巨噬细胞是炎症介质的主要来源，包括抑制FGF-10表达和气道形态发生的IL-1？。然而，关于这一机制仍存在一些问题。首先，似乎有一个发育窗口期的易感性，在此期间炎症可以改变胎肺形态发生。对早期阶段缺乏影响可能是由于未成熟的肺巨噬细胞无法对微生物刺激做出反应或释放炎症介质（如IL-1）的效率低下。作为炎症反应的一部分，多蛋白炎性体复合物加工并释放IL-1？。初步的数据表明，表达和功能的炎性体可能是发展调节。除了围绕巨噬细胞反应成熟的问题外，炎症介质如何破坏靶间充质细胞中正常发育基因的表达尚不清楚。最近的数据显示，NF-？B破坏转录因子Sp1和Sp3对FGF-10启动子活性的正常调节。NF-之间的相互作用？B亚基RelA和Sp3似乎将Sp3转化为转录阻遏物。该提案包括三个具体目标，以检查连接炎症和异常肺发育的细胞和分子机制。第一个目标是确定肺巨噬细胞先天免疫反应的哪些方面是发育调节的。第二个目标是测试是否需要炎性小体功能和半胱天冬酶介导的IL-1？加工，并足以抑制肺气道形态发生。第三个目标是进一步研究NF-？B和FGF-10表达变化。这些研究将更好地确定炎症如何影响肺形态发生，并确定潜在的目标，以开发新的治疗策略，预防和治疗早产儿BPD。