Regulation of Integrin Function

University Of California, San Francisco, San Francisco CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Alveolar epithelial cells (AEC) contribute to lung injury responses by proliferating, regulating matrix resorption, and presenting active TGFbeta1 to fibroblasts, promoting their conversion to myofibroblasts. AEC may also exercise their own plasticity to become fibroblast-like in their invasiveness and matrix production. However, regulation of cellular responses to TGFbeta1 and the potential of AEC to undergo epithelial to mesenchymal-like transitions (EMT) in the lung are poorly understood. While TGFbeta1 signaling is critical to these processes, TGFbeta1 signaling alone appears insufficient to affect fibrogenesis. Recent findings show that epithelial cell EMT responses to TGFbeta1 require beta1 integrins and especially the integrin alpha2beta1. These observations lead to the hypothesis that beta1 integrins act as a critical sensor in TGFbeta1 signaling. It is further proposed that in AEC alpha3beta1, a laminin receptor, is the key regulatory beta1 integrin which mediates TGFbeta1 driven epithelial cell plasticity and mesenchymal transition in the context of lung matrix remodeling. This hypothesis is addressed in the application through a series of studies which use either RNAi knockdown or alveolar epithelial cells with inducible deletion of alpha3beta1 via cre recombinase to elucidate how integrins regulate SMAD signaling. The presence of EMT in models of murine fibrogenesis in vivo will be examined in mice expressing either galactosidase or EGFP selectively in lung epithelial cells and the role of alpha3beta1 in the process defined by studies of fibrogenesis in mice with conditional deletion of AEC alpha3beta1. Elucidation of a pathway of integrin signaling controlling AEC responses to (1 and definition of the capacity of AEC to transition to fibroblasts during matrix remodeling should provide new insight into the pathobiology of pulmonary fibrosis.