IPF Fibroblast Phenotype

特发性肺纤维化(IPF)是一种对药物治疗无效的慢性进行性肺部疾病。除非接受肺移植治疗，否则每10,000人中就有1人在确诊后3-5年内死亡。为了阻止这种致命的疾病，本计划项目重点研究纤维增殖过程及其关键细胞成分-肌成纤维细胞。尽管研究表明IPF成纤维细胞表现出不同的病理表型，但对于导致进行性纤维化的IPF肌成纤维细胞的病理性质与正常组织修复所必需的肌成纤维细胞的生理功能之间的差异，仍存在很大的认识空白。考虑到这一点，组成这一PPG的各个项目促进了一个统一的主题：通过揭示导致IPF持续纤维化的肌成纤维细胞细胞机制的组件，以及在正常情况下的适当组织愈合，提供对导致IPF成纤维细胞异常的分子过程的直接机械洞察力。我们的理论是，细胞因子和基质大分子的恶意结合调节成纤维细胞的表型，导致基本的成纤维细胞细胞器发生稳定的病理变化，这些变化可以在转录、翻译和信号转导水平上辨别出来。在这个框架内，项目1(Henke)研究整合素-基质在调节IPF成纤维细胞增殖中的作用；项目2(Bitterman)研究IPF中成纤维细胞表型的翻译控制；项目3(Phan)评估肌成纤维细胞分化的转录控制。科学部门由一个行政核心(Henke)和一个生物显微镜和组织病理学核心(Ingbar)提供支持。Biospecimen Core的功能是提供标准化的组织标本和细胞系，供每个研究人员使用，以减少在细胞分离和培养过程中可能出现的成纤维细胞表型的不受控制的变化。因此，该计划项目聚集了一群拥有不同专业领域的科学家，共同致力于一个共同的主题。该计划项目的一个主要目标是通过提供可转化为IPF新的治疗策略的信息，为IPF临床网络的决策提供信息。

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease refractory to pharmacological therapy. It afflicts 1/10,000 individuals leading to death within 3-5 years of diagnosis unless treated by lung transplantation. In attempt to arrest this lethal disease, this Program Project focuses on the fibroproliferative process and its key cellular constituent- the myofibroblast. Despite studies indicating that IPF fibroblasts display a distinct pathological phenotype, large gaps in knowledge remain regarding differences between the pathological nature of IPF myofibroblasts responsible for progressive fibrosis and the physiological function of myofibroblasts essential for normal tissue repair. Considering this, the individual projects comprising this PPG promote a unified theme: provide direct mechanistic insight into the molecular processes that make an IPF fibroblast abnormal by uncovering components of the myofibroblast cellular machinery that result in unrelenting fibrosis in IPF, and in proper tissue healing under normal circumstances. It is our theory that a malicious alliance of cytokines and matrix macromolecules modulates the fibroblast phenotype resulting in stable pathological changes in the basic fibroblast cellular machinery that can be discerned at the level of transcription, translation and signal transduction. Within this framework, Project 1 (Henke) examines the role of integrin-matrix in regulating IPF fibroblast proliferation; Project 2 (Bitterman) investigates translational control of the fibroblast phenotype in IPF; and Project 3 (Phan) assesses transcriptional control of myofibroblast differentiation. The scientific sections are supported by an Administrative Core (Henke) and a Biospecimen and Histopathology Core (Ingbar). The Biospecimen Core functions to provide standardized tissue specimens and cell lines to be used by each investigator in order to reduce uncontrolled alterations in fibroblast phenotype possible during cell isolation and cultivation. Thus, this Program Project has gathered a group of scientists with diverse areas of expertise to work together on a common theme. A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF.