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.
The interactions between epithelial cells and the extracellular matrix are crucial for epithelial function during lung development. We have identified extracellular matrix integrin receptors, a3 and a6 integrin, that are required for normal lung branching and epithelial differentiation. In this proposal, we will determine the mechanisms by which a3 and a6 integrins are required for lung branching morphogenesis and define major pathways by which laminin binding integrins regulate epithelial cell behavior during alveolarization, which may lead to new approaches to promote lung development and health.