Laminin Alpha 1 in Lung Development and Repair

描述(申请人提供)：主要基于体外研究，层粘连蛋白α1被认为在早期肺发育中发挥重要作用，但它在正常成年小鼠或人肺中不表达。然而，我们最近检测到层粘连蛋白α1在博莱霉素诱导的肺损伤后的成年小鼠肺中的表达。这项建议的具体目的1是确定层粘连蛋白α1在肺发育和修复中的体内作用。传统的层粘连蛋白α1基因敲除小鼠在E5死亡，在肺芽形成之前。因此，我们将发展条件性层粘连蛋白α1基因敲除小鼠。利用这些小鼠和强力环素诱导的cre/lox系统，我们可以获得层粘连蛋白α1表达的时空控制性。我们将使用这个系统来调节层粘连蛋白α1在肺发育的不同阶段和博莱霉素诱导的肺损伤期间的表达。这些研究将确定层粘连蛋白α1的缺失如何影响肺的发育和修复。为了阐明层粘连蛋白在弥漫性肺泡损伤后肺泡再上皮化中的作用机制，特异的AIM2将集中在层粘连蛋白-1和-10在上皮细胞增殖、迁移和分化中的作用。更好地了解层粘连蛋白等BM成分在肺发育和修复中的作用，将提高弥漫性肺泡损伤后促进肺结构和功能恢复的能力。

DESCRIPTION (provided by applicant): Based primarily on in vitro studies, laminin alpha1 is believed to play important roles in early lung development, yet it is not expressed in normal adult mouse or human lung. However, we recently detected laminin alpha1 expression in adult mouse lungs following bleomycin-induced lung injury. SPECIFIC AIM 1 of this proposal is to define in vivo roles for laminin alpha1 in lung development and repair. Conventional laminin alpha1 knockout mice die at E5, prior to lung bud formation. Therefore, we will develop conditional laminin alpha1 knockout mice. With these mice and a doxycycline-inducible cre/lox system, we can obtain temporal-spatial control of laminin alpha1 expression. We will use this system to regulate laminin alpha1 expression at various stages of lung development and during bleomycin-induced lung injury. These studies will determine how the absence of laminin alpha1 affects lung development and repair. To elucidate the mechanisms by which laminins play roles in alveolar re-epithelialization following diffuse alveolar damage, SPECIFIC AIM 2 will focus on the roles of laminins-1 and -10 in epithelial cell proliferation, migration, and differentiation. Better understanding of the role of BM components like laminins in lung development and repair will enhance the ability to promote restoration of lung structure and function after diffuse alveolar damage.