Proper organogenesis requires assimilation of microenvironmental cues from the extracellular matrix (ECM). Integrins mediate epithelial cell-ECM interactions in branched organs and guide coordinated epithelial cell proliferation, migration, and differentiation, processes critical for development and repair after injury. Congenital integrin mutations result in kidney, mammary, and submandibular gland hypoplasia and, in the kidney, also modulate the fibrotic response to injury. Recently, disrupted cell-ECM interactions due to integrin a3 subunit mutations have been shown to cause lung hypoplasia/dysplasia in humans. However, very little is known about how cell-ECM interactions regulate lung development and repair. Most of our knowledge about cell-ECM interactions in the lung is based on the study of laminins, critical components of the lung basement membrane. Transgenic murine models clearly demonstrate that specific laminin chains are required for lung branching morphogenesis and human mutations in the laminin a2, a5, and 1 genes are associated with lung disease. Integrins, which are comprised of an a and subunit, form the principal laminin and collagen receptors in the lung with the 1 subunit being the common subunit in these receptors. Deleting 1 removes nearly all the ECM receptors from the lung epithelium. We recently deleted 1 integrin specifically in the murine lung epithelium at E10.5, P0, and P28 to investigate the role of cell-ECM interactions during lung development. Loss of 1 integrin at E10.5 impaired both branching morphogenesis and alveolarization. Deleting 1 integrin at P0 resulted in only an alveolarization defect and deletion of 1 integrin at P28, afte the completion of alveolarization, resulted in normal lungs but increased susceptibility to mechanical stress-induced injury. These findings indicate that epithelial 1 integrin plays distint roles during both alveolarization and post-development. One of our key findings was that epithelial 1 integrin regulated septation, epithelial differentiation and macrophage infiltration during alveolarization. Further in vitro studies with 1 integrin null epithelial cells suggested hat 1 regulated macrophage accumulation by increasing production of reactive oxygen species and monocyte chemoattractant protein-1, the main chemoattractant for lung macrophages. The mechanisms whereby 1 integrin expression regulates the fundamental processes required for normal alveolarization and homeostasis are unknown. In this grant we will use our novel model of temporal deletion of lung epithelial 1 integrin to test the hypothesis that epithelial 1 intgrin regulates secondary septation during early alveolarization and maintains alveolar homeostasis in the adult lung by regulating lung inflammation and epithelial differentiation.
AIM 1. Determine the mechanism whereby 1 integrin-dependent cell-ECM interactions regulate secondary septation.
AIM 2. Determine the mechanism whereby epithelial 1 integrin is required for alveolar homeostasis.

Public Health Relevance

Impaired lung development puts certain infants at risk for significant respiratory morbidity or mortality when paired with an additional risk factr, such as prematurity. We have identified an extracellular matrix receptor, 1 integrin, that is required for normal alveolarization. In this proposal, we will determine the mechanism by which 1 integrin regulates alveolar septation, which may lead to new approaches to promote lung development and health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL127102-04
Application #
9479263
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Colombini-Hatch, Sandra
Project Start
2016-05-01
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
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Plosa, Erin J; Young, Lisa R; Gulleman, Peter M et al. (2014) Epithelial ?1 integrin is required for lung branching morphogenesis and alveolarization. Development 141:4751-62