IPF Fibroblast Phenotype

IPF 成纤维细胞表型

• 批准号: 8242760
• 负责人: CRAIG A HENKE
• 金额: $ 167.31万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242760
• 关键词: Alveolar; Alveolus; Anti-Inflammatory Agents; Anti-inflammatory; Area; Behavior; Bronchiolitis Obliterans Organizing Pneumonia; Cell Death; Cell Line; Cell Separation; Cell physiology; Cells; Cessation of life; Characteristics; Chronic; Cicatrix; Clinical; Collagen Type I; Data; Deposition; Diagnosis; Disease; Disease Progression; Educational workshop; Epithelial; Epithelial Cells; Facies; Fibroblasts; Fibrosis; Future; Genetic Transcription; Goals; Hamman-Rich syndrome; Healed; Heart; Histopathology; Individual; Inflammation; Injury; Integrins; Integumentary system; Interstitial Lung Diseases; Kidney; Knowledge; Lead; Lesion; Liver; Lung; Lung Transplantation; Lung diseases; Mind; Molecular; Myofibroblast; National Heart, Lung, and Blood Institute; Nature; Normal tissue morphology; Outcome; Pathogenesis; Pathology; Phenotype; Physiological; Process; Prognostic Factor; Progressive Disease; Proliferating; Refractory; Regulation; Research; Research Personnel; Research Project Grants; Role; Science; Scientist; Sentinel; Signal Transduction; Specimen; Staging; Tissues; Transcriptional Regulation; Translating; Translations; Work; cell injury; cytokine; effective therapy; epithelial to mesenchymal transition; healing; insight; lung repair; macromolecule; novel therapeutics; programs; response; theories; tissue repair

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.

特发性肺纤维化（IPF）是一种药物治疗难治的慢性进行性肺部疾病。除非通过肺移植治疗，否则有 1/10,000 的个体会在诊断后 3-5 年内死亡。为了阻止这种致命疾病，该项目重点关注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 成纤维细胞表现出独特的病理表型，但关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，仍然存在巨大的知识差距。考虑到这一点，组成该 PPG 的各个项目促进了一个统一的主题：通过揭示肌成纤维细胞机制的组成部分，提供对导致 IPF 成纤维细胞异常的分子过程的直接机制洞察，这些机制导致 IPF 中无情的纤维化，并在适当的组织愈合下正常情况下。我们的理论是，细胞因子和基质大分子的恶意联盟调节成纤维细胞表型，导致基本成纤维细胞细胞机制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。在此框架内，项目 1 (Henke) 研究了整合素基质在调节 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。科学部分由行政核心 (Henke) 和生物样本和组织病理学核心 (Ingbar) 提供支持。生物样本核心的功能是提供每位研究者使用的标准化组织样本和细胞系，以减少细胞分离和培养过程中可能出现的成纤维细胞表型不受控制的变化。因此，该计划项目聚集了一群具有不同专业领域的科学家，为一个共同的主题而共同努力。该计划项目的一个主要目标是通过提供可转化为 IPF 新型治疗策略的信息，为 IPF 临床网络的决策提供信息。