Laminin Binding Integrins in Lung Development

项目总结 我们研究计划的总体目标是确定细胞-细胞外基质(ECM)相互作用是如何调节的 健康和疾病中的肺发育和肺泡动态平衡。上皮细胞与 通过整合素包围细胞外基质，跨膜蛋白受体由a和b亚基组成。 整合素是上皮细胞和细胞外基质之间的信号转导所必需的，并调节关键的细胞过程。 如黏附、迁移、增殖、分化和细胞存活。层粘连蛋白是主要的 肺基底膜的成分，是一种专门的细胞外基质结构。层粘连蛋白结合整合素是 其他分支器官如肾脏、乳腺和下颌下器官的器官发生所必需的 腺体，但在肺中的研究相对较少。整合素在时间和空间上以特定的方式表达 影响其ECM配体结合亲和力的方式。精确的层粘连蛋白-整合素相互作用调节 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a3b1和a6b1 作为肺发育中的关键整合素。我们的小鼠肺上皮中a6整合素的缺失 证明了在早期肺分支形态发生中的关键作用。新航空公司在压力点有分支， 上皮细胞必须停止并旋转，以推动呼吸道生长向新的方向发展。在他们作为 机械感受器、整合素完全可以引导上皮细胞生长的速度和方向。 整合素还可以在肺泡微环境中发出信号，影响上皮细胞的行为。删除A3 在小鼠的肺中，会导致囊状、肺泡化和上皮分化缺陷。上皮性 分化是适当的肺泡化和上皮对损伤的反应所必需的。我们之前已经 研究表明，上皮b1整合素与a3整合素结合是正常上皮细胞反应所必需的。 受伤后。因此，在这个建议中，我们将检验a6b1整合素是主要层粘连蛋白的假设。 A3b1是调节分枝形态发生的受体，而a3b1则是肺泡化所必需的。 目的1：确定层粘连蛋白结合整合素在分支形态发生中的具体作用。 目的2：明确层粘连蛋白结合整合素在囊化和肺泡化过程中的作用。

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.