Laminin Binding Integrins in Lung Development

肺发育中的层粘连蛋白结合整合素

基本信息

  • 批准号:
    10229619
  • 负责人:
  • 金额:
    $ 8.6万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-05 至 2022-07-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY The overall goal of our research program is to define how cell-extracellular matrix (ECM) interactions regulate lung development and alveolar homeostasis in health and disease. Epithelial cells connect with the surrounding ECM through integrins, transmembrane protein receptors comprised of an a and b subunit. Integrins are required for signaling between epithelial cells and the ECM and regulate critical cell processes, such as adhesion, migration, proliferation, differentiation and cell survival. Laminin is one of the major components of the lung basement membrane, a specialized ECM structure. Laminin binding integrins are required for organogenesis in other branched organs such as the kidney, mammary gland, and submandibular gland, but are relatively understudied in the lung. Integrins are expressed in a temporally and spatially specific manner that influences their ECM ligand binding avidity. The precise laminin-integrin interactions that regulate fetal lung development are currently unknown. From our preliminary work, we have identified a3b1 and a6b1 as the critical integrins in lung development. Our murine deletion of a6 integrin in the lung epithelium demonstrates a critical role in early lung branching morphogenesis. New airways branch at pressure points, where epithelial cells must stop and pivot to advance airway growth in a new direction. In their role as mechanoreceptors, integrins are perfectly poised to direct the speed and direction of epithelial growth. Integrins also signal changes in the alveolar microenvironment and influence epithelial behavior. Deletion of a3 in the murine lung results in sacculation, alveolarization, and epithelial differentiation defects. Epithelial differentiation is required for proper alveolarization and the epithelial response to injury. We have previously shown that epithelial b1 integrin, binding partner to a3 integrin, is required for the normal epithelial response after injury. Thus, in this proposal, we will test the hypothesis that a6b1 integrin is the dominant laminin receptor for regulation of branching morphogenesis, whereas a3b1 is required for alveolarization. AIM 1: Determine the specific roles for laminin binding integrins in branching morphogenesis. AIM 2: Define the role of laminin binding integrins during sacculation and alveolarization.
项目摘要 我们研究计划的总体目标是确定细胞-细胞外基质(ECM)相互作用如何调节 健康和疾病中的肺发育和肺泡稳态。上皮细胞与 通过整联蛋白(由a和B亚基组成的跨膜蛋白受体)包围ECM。 整合素是上皮细胞和ECM之间的信号传导所必需的,并调节关键的细胞过程, 例如粘附、迁移、增殖、分化和细胞存活。层粘连蛋白是一种主要的 肺基底膜的组成部分,一个专门的ECM结构。层粘连蛋白结合整联蛋白是 其他分支器官如肾脏、乳腺和下颌下的器官发生所需的蛋白质 腺体,但在肺中相对研究不足。整合素以时间和空间特异性的方式表达, 影响其ECM配体结合亲合力的方式。层粘连蛋白-整合素的相互作用, 胎儿肺发育目前尚不清楚。从我们的初步工作中,我们已经确定了a3 b1和a6 b1 作为肺发育中的关键整合素。我们的小鼠肺上皮中α 6整合素的缺失 在早期肺分支形态发生中起关键作用。压力点处的新气道分支, 上皮细胞必须停止并转向新的方向促进气道生长。在他们的角色, 作为机械感受器,整合素完全准备好引导上皮生长的速度和方向。 整合素也信号改变肺泡微环境和影响上皮细胞的行为。删除a3 导致囊状形成、肺泡化和上皮分化缺陷。上皮 分化对于适当的肺泡化和上皮对损伤的反应是必需的。我们先前已经 表明正常上皮反应需要上皮b1整联蛋白(a3整联蛋白的结合伴侣) 伤后因此,在本研究中,我们将检验a6 b1整合素是主要层粘连蛋白的假设。 受体调节分支形态发生,而a3 b1是肺泡化所需的。 目的1:确定层粘连蛋白结合整合素在分支形态发生中的特殊作用。 目的2:明确层粘连蛋白结合整合素在肺泡形成过程中的作用。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Erin J Plosa其他文献

Erin J Plosa的其他文献

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{{ truncateString('Erin J Plosa', 18)}}的其他基金

Integrins in the Developing Lung
发育中的肺中的整合素
  • 批准号:
    10420896
  • 财政年份:
    2022
  • 资助金额:
    $ 8.6万
  • 项目类别:
Integrins in the Developing Lung
发育中的肺中的整合素
  • 批准号:
    10674710
  • 财政年份:
    2022
  • 资助金额:
    $ 8.6万
  • 项目类别:
Laminin Binding Integrins in Lung Development
肺发育中的层粘连蛋白结合整合素
  • 批准号:
    10064461
  • 财政年份:
    2020
  • 资助金额:
    $ 8.6万
  • 项目类别:

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