Periostin induces matrix stiffness and epithelial cell mesenchymal transition

描述（由申请人提供）：肺纤维化疾病，包括特发性肺纤维化（IPF），其特征是成纤维细胞积聚、胶原过度沉积和基质重塑，导致正常肺泡结构破坏。常驻成纤维细胞群体的扩张和肺泡上皮细胞通过上皮-间质转化（EMT）的过程形成成纤维细胞被认为是对有害刺激的反应；然而，这一过程的发病机制尚不清楚。特发性肺纤维化发病机制迫切需要新的分子靶点，因为目前还没有已知的治疗方法来逆转或停止疾病的进展。骨膜蛋白是一种上皮细胞产物，似乎在肺纤维化中起作用。在特发性肺纤维化患者和暴露于肺纤维化实验模型的小鼠的肺组织中，骨膜蛋白增加。在转化和原代人气道上皮细胞的研究中，骨膜蛋白过表达导致TGF-2上调，I型胶原蛋白的产生增加，并诱导EMT。此外，已知骨膜蛋白结合1型胶原并增加其弹性，表明它在胶原交联和基质刚度中起作用。综上所述，这些初步数据使我们假设骨膜蛋白是一种新的肺纤维化介质，通过其对胶原交联和基质硬化的影响，随后在肺内诱导EMT。该研究项目旨在确定1)骨膜蛋白过表达对不同硬度基质上生长的小鼠肺泡上皮细胞的影响；2)建立负责与1型胶原相互作用的骨膜蛋白结构域。总之，这些研究将进一步深入了解肺纤维化的发病机制，并可能为该疾病的未来治疗提供新的治疗靶点。

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. )