Periostin induces matrix stiffness and epithelial cell mesenchymal transition

骨膜素诱导基质硬度和上皮细胞间质转化

基本信息

批准号：
8058441
负责人：
Erin D. Gordon
金额：
$ 5.68万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8058441
关键词：
Affinity Alveolar Antibodies Architecture Asthma Binding Biological Assay Biomechanics Bleomycin C-terminal Cells Cessation of life Collagen Collagen Type I Data Deposition Development Diagnosis Disease Disease Progression E-Cadherin Elasticity Epithelial Epithelial Cells Etiology Experimental Models Extracellular Matrix Fibroblasts Fibronectins Fibrosis Future Gene Expression Genes Grant Hamman-Rich syndrome Human Immunoblotting Integrins Lead Length Lentivirus Vector Link Lung Lung diseases Measures Mediating Mediator of activation protein Mesenchymal Methods Molecular Target Mus Pathogenesis Patients Play Population Process Production Property Proteins Pulmonary Fibrosis Research Project Grants Reverse Transcriptase Polymerase Chain Reaction Role Stimulus Structure of parenchyma of lung Techniques Tertiary Protein Structure Up-Regulation Vimentin airway epithelium crosslink cytokine density effective therapy inhibitor/antagonist insight mutant new therapeutic target novel overexpression periostin peripheral blood polyacrylamide gels response response to injury

项目摘要

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. )

描述（由申请人提供）：肺部纤维化疾病，包括特发性肺纤维化（IPF），其特征是成纤维细胞积聚、胶原蛋白过度沉积和基质重塑，导致正常肺泡结构的破坏。人们认为，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）过程发展成纤维化成纤维细胞都是对有害刺激的反应。然而，这一过程的发病机制仍不清楚。由于目前尚无已知的疗法可以逆转或阻止疾病的进展，因此迫切需要针对特发性肺纤维化发病机制的新分子靶点。骨膜素是一种上皮细胞产物，似乎在肺纤维化中发挥作用。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素蛋白均增加。在对转化和原代人气道上皮细胞的研究中，periostin 过度表达会导致 TGF-2 上调，增加 I 型胶原蛋白的产生，并诱导 EMT。此外，众所周知，骨膜素可以结合 1 型胶原蛋白并增加其弹性，这表明它在胶原蛋白交联和基质刚度方面发挥着作用。综上所述，这些初步数据使我们推测骨膜素通过影响胶原交联和基质硬化以及随后诱导肺内 EMT 而成为肺纤维化的新型介质。拟议的研究项目将寻求确定 1) 骨膜素过度表达对在不同硬度的基质上生长的小鼠肺泡上皮细胞的影响，以及 2) 建立负责与 1 型胶原蛋白相互作用的骨膜素结构域。总之，这些研究将进一步深入了解肺纤维化的发病机制，并可能为未来治疗该疾病提供新的治疗靶点。公共卫生相关性：特发性肺纤维化是一种病因不明的进行性致残性肺部疾病，在诊断后 2-3 年内迅速导致死亡。没有已知的有效疗法来治疗这种疾病。该项目旨在阐明骨膜素蛋白在肺纤维化发病机制中的作用，从而可能产生新的治疗靶点。）