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: 9278222
• 负责人: Lawrence S Prince
• 金额: $ 45.67万
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9278222
• 关键词: Address; Affect; Agonist; Alleles; Animal Model; Architecture; Biochemical; Bronchopulmonary Dysplasia; 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; Exposure to; FGF10 gene; Family; Fetal Lung; Gene Expression; Gene Expression Regulation; Genetic Transcription; Growth Factor; Health; Hospitalization; Incidence; Infant; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Innate Immune System; Interleukin-1 beta; Knock-in Mouse; Knockout Mice; Lead; Link; Lung; Macrophage Activation; Mediating; Mesenchymal; Mesenchyme; Modeling; Molecular; Molecular Models; Morphogenesis; Mus; Neonatology; Pathogenesis; Patients; Predisposition; Pregnancy; Premature Birth; Premature Infant; Prevention strategy; Process; Production; Proteins; Recurrence; Regulation; Respiratory physiology; Risk; Role; Signal Transduction; Source; Sp1 Transcription Factor; Stimulus; Testing; Toll-like receptors; Transcription Repressor/Corepressor; activating transcription factor; cytokine; experimental study; extreme prematurity; fetal; gain of function; improved; insight; lung development; macrophage; microbial; molecular modeling; mouse model; mutant; neonatal care; novel therapeutic intervention; novel therapeutics; overexpression; prevent; promoter; public health relevance; receptor expression; 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-κB 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-1ß 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-1ß. As part of the inflammatory response, multi-protein inflammasome complexes process and release IL-1ß. 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-κB disrupts the normal regulation of FGF-10 promoter activity by the transcription factors Sp1 and Sp3. Interactions between the NF-κB 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-1ß processing is required and sufficient to inhibit lung airway morphogenesis. The third aim will further investigate the molecular mechanisms linking NF-κB 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）：早产仍然是产科和新生儿学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，影响到高达50%的妊娠28周前出生的早产儿。由于发育受阻，BPD患者的肺缺少正常数量的囊状气道和成熟肺泡。目前的临床和实验证据表明，BPD患者肺部发育受阻可能是由于炎症和随后炎症介质的释放。BPD患者肺部的关键生长因子FGF-10水平也有所降低。

项目成果

Paneth cell ablation in the presence of Klebsiella pneumoniae induces necrotizing enterocolitis (NEC)-like injury in the small intestine of immature mice.

• DOI: 10.1242/dmm.009001
• 发表时间: 2012-07
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: Zhang C;Sherman MP;Prince LS;Bader D;Weitkamp JH;Slaughter JC;McElroy SJ
• 通讯作者: McElroy SJ

The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity.

• DOI: 10.1152/ajplung.00554.2016
• 发表时间: 2017-06
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Rachel M. Medal;Amanda M. Im;Yasutoshi Yamamoto;O. Lakhdari;T. Blackwell;H. Hoffman;D. Sahoo;L. Prince