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IPF Fibroblast Phenotype

IPF 成纤维细胞表型

基本信息

批准号：
8450884
负责人：
CRAIG A HENKE
金额：
$ 159.28万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450884
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

项目摘要

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）是一种慢性进行性肺部疾病，药物治疗难治性。除非通过肺移植治疗，否则该病会在确诊后3-5年内导致1/10,000人死亡。为了阻止这种致命的疾病，这个项目的重点是纤维增殖过程及其关键的细胞成分-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，知识上仍然存在很大差距。考虑到这一点，组成PPG的各个项目促进了一个统一的主题：通过揭示导致IPF中持续纤维化和正常情况下适当组织愈合的肌成纤维细胞细胞机制的组成部分，为使IPF成纤维细胞异常的分子过程提供直接的机制见解。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，导致成纤维细胞基本细胞机制的稳定病理变化，这些变化可以在转录，翻译和信号转导水平上识别。在此框架下，Project 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）研究了IPF中成纤维细胞表型的翻译控制；项目3 （Phan）评估了肌成纤维细胞分化的转录控制。科学部分由行政核心（Henke）和生物标本和组织病理学核心（Ingbar）支持。生物标本核心的功能是提供标准化的组织标本和细胞系，供每个研究者使用，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改变。因此，该计划项目聚集了一群具有不同专业领域的科学家，共同研究一个共同的主题。该项目的一个主要目标是通过提供可转化为IPF新治疗策略的信息，为IPF临床网络的决策提供信息。