Periostin induces matrix stiffness and epithelial cell mesenchymal transition

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Fibrotic diseases of the lung, including idiopathic pulmonary fibrosis (IPF), are characterized by fibroblast accumulation, excessive collagen deposition, and matrix remodeling, leading to the destruction of normal alveolar architecture. Both expansion of the resident fibroblast population and development of fibrogenic fibroblasts from lung alveolar epithelial cells through a process known as epithelial-mesenchymal transition (EMT) is thought to occur in response to injurious stimuli; however, the pathogenesis of this process remains unknown. Novel molecular targets for the pathogenesis of idiopathic pulmonary fibrosis are desperately needed, as there is currently no known therapy to reverse or halt the progression of disease. Periostin, an epithelial cell product, appears to play a role in pulmonary fibrosis. Periostin protein is increased in the lung tissue of both patients with idiopathic pulmonary fibrosis and mice exposed to an experimental model of pulmonary fibrosis. In studies of both transformed and primary human airway epithelial cells, periostin over-expression causes upregulation of TGF-2, increased production of type I collagen, and induction of EMT. Furthermore, periostin is known to bind type 1 collagen and increase its elasticity, indicating that it plays a role in collagen crosslinking and matrix stiffness. Taken together, these preliminary data lead us to hypothesize that periostin is a novel mediator of pulmonary fibrosis via its effects on collagen crosslinking and matrix stiffening and, subsequently, the induction of EMT within the lung. The proposed research project will seek to determine 1) the effects of periostin overexpression on murine alveolar epithelial cells grown on matrices of varying stiffness and 2) establish the periostin domain responsible for interaction with type 1 collagen. Together, these studies will offer further insight into the pathogenesis of pulmonary fibrosis and may yield a novel therapeutic target for future treatment of the disease. PUBLIC HEALTH RELEVANCE: Idiopathic pulmonary fibrosis is a progressive and disabling lung disease of unknown etiology that rapidly leads to death within 2-3 years of diagnosis. There are no known effective therapies to treat this disease. This project aims to elucidate the role of periostin protein in the pathogenesis of pulmonary fibrosis, potentially leading to new therapeutic targets. )