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标题:FGF18对出生后肺发育的调节 摘要: 肺泡形成是肺发育的最后阶段,肺的表面积增加 通过形成次级隔膜(隔脊)来细分肺泡囊,然后变薄 隔壁产生一个高效的空气/血液气体交换器官。支气管肺发育不良(BPD)是一种 肺泡发育受阻的早产的常见并发症。BPD通常会导致慢性 呼吸道疾病。然而,除了维生素A和支持性护理外,没有任何治疗方法可以促进肺泡形成 以及血管发育,以改善患有BPD的婴儿的预后。 人类和啮齿动物的肺泡发育可分为两个阶段。在第一阶段,肺泡 肌成纤维细胞(AMFS)和其他间充质细胞和上皮细胞调节次级隔的形成。 在第二阶段,隔壁经历了一个成熟的过程,这个过程包括变薄,通过失去 间充质细胞和微血管系统的重塑,形成单层毛细血管网络 肺泡I型(AT1)细胞。成熟的肺泡壁确保了成人肺内有效的空气/血液气体交换。 深入了解调节肺泡间隔和间隔壁成熟的机制将是 需要为患有BPD的早产儿开发治疗方法,并为成人开发潜在的治疗方法 肺再生。然而,关于间充质祖细胞的身份存在具体的知识空白。 AMFS和其他间质细胞类型的功能,以及AMFS的机制 在二次间隔完成时终止并清除肺中的AMFS。 成纤维细胞生长因子18(Fgf18)在肺泡形成过程中在AMFS和AT1细胞中高水平表达。 我们发现,新生儿肺组织中Fgf18的条件失活会导致肺泡形成功能受损。穿过 对Fgf18表达细胞的谱系追踪,我们发现AMF在第一阶段后从肺中清除。 肺泡形成,与肺泡壁变薄一致,但AT1细胞保留。 在这项建议中,我们使用了一种独特的遗传工具的组合来追踪谱系和基因失活,细胞 分选结合RNA深度测序,以及单细胞和单核RNA测序,以鉴定 间充质和上皮性FGF18在肺泡形成的第一和第二阶段的相对贡献 细胞对FGF18的反应(S)在肺泡形成过程中,产生成纤维细胞亚型的祖细胞 肺泡间隔,以及从肺中特异性清除AMFS的机制。拟议中的实验将 还可以生成在肺泡形成过程中存在的间隔间充质细胞类型的基因表达图谱 将作为研究界的资源。
英文摘要
Title: FGF18 regulation of postnatal lung development Summary: Alveologenesis is the final stage of lung development where the surface area of the lung is increased by subdividing alveolar saccules through the formation of secondary septae (septal ridges), followed by thinning of the septal walls to generate an efficient air/blood gas exchange organ. Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth in which alveologenesis is impaired. BPD often results in chronic respiratory disease. However, besides Vitamin A and supportive care, no therapies exist to promote lung alveolar and vascular development to improve the outcomes of infants with BPD. Alveologenesis can be divided into two phases in humans and rodents. During the first phase, alveolar myofibroblasts (AMFs) and other mesenchymal and epithelial cells regulate the formation of secondary septae. During the second phase, the septal walls undergo a maturation process that involves thinning, through loss of mesenchymal cells and remodeling of the microvasculature, to a single layer capillary network juxtaposed with alveolar type 1 (AT1) cells. The mature alveolar wall ensures efficient air/blood gas exchange in the adult lung. An in-depth understanding the mechanisms that regulate alveolar septation and septal wall maturation will be required to develop therapies for premature infants with BPD and for developing potential therapies for adult lung regeneration. However, there are specific knowledge gaps about the identity of mesenchymal progenitors that give rise to AMFs, the functions of AMFs and other mesenchymal cell types, and the mechanisms that terminate and clear AMFs from the lung at the completion of secondary septation. Fibroblast Growth Factor 18 (Fgf18) is expressed at high levels in AMFs and AT1 cells during alveologenesis. We show that conditional inactivation of Fgf18 in the neonatal lung results in impaired alveologenesis. Through lineage tracing of Fgf18-expressing cells, we find that the AMFs are cleared from the lung after the first phase of alveologenesis, coinciding with alveolar wall thinning, but that AT1 cells are retained. In this proposal, we use a combination of unique genetic tools for lineage tracing and gene inactivation, cell sorting coupled with RNA deep sequencing, and single cell and single nuclei RNA sequencing, to identify the relative contribution of mesenchymal and epithelial FGF18 to the first and second phases of alveologenesis, the cellular response(s) to FGF18 during alveologenesis, the progenitors that give rise to fibroblasts sub-types in alveolar septae, and the mechanisms that specifically clear AMFs from the lung. The proposed experiments will also generate an atlas of gene expression for septal mesenchymal cell types present during alveologenesis that will serve as a resource for the research community.
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Identification of an FGF-regulated signaling center in the Groove of Ranvier that controls longitudinal bone growth.
  • 批准号:
    10667798
  • 项目类别:
  • 资助金额:
    $20.55万
  • 财政年份:
    2023
  • 负责人:
    David M Ornitz
  • 依托单位:
Regulation of Osteocyte Survival by Fibroblast Growth Factor Signaling Pathways
  • 批准号:
    10391803
  • 项目类别:
  • 资助金额:
    $52.41万
  • 财政年份:
    2022
  • 负责人:
    David M Ornitz
  • 依托单位:
LTBP2 regulation of fibrotic lung damage
  • 批准号:
    10633230
  • 项目类别:
  • 资助金额:
    $19.46万
  • 财政年份:
    2022
  • 负责人:
    David M Ornitz
  • 依托单位:
LTBP2 regulation of fibrotic lung damage
  • 批准号:
    10526774
  • 项目类别:
  • 资助金额:
    $23.63万
  • 财政年份:
    2022
  • 负责人:
    David M Ornitz
  • 依托单位:
国内基金
海外基金
湍流和化学交互作用对H2-Air-H2O微混燃烧中NO生成的影响研究
  • 批准号:
    51976048
  • 项目类别:
    面上项目
  • 资助金额:
    61.0万元
  • 批准年份:
    2019
  • 负责人:
    邱朋华
  • 依托单位: