IPF Fibroblast Phenotype

IPF 成纤维细胞表型

• 批准号: 8034790
• 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/8034790
• 关键词: IPF; Fibroblast; Phenotype

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，进行性肺部疾病对药理治疗的难治。除非通过肺移植治疗，否则它会在诊断3 - 5年内遭受1/10,000名导致死亡的人。为了阻止这种致命疾病，该计划项目的重点是纤维增生过程及其关键细胞成分 - 肌纤维细胞。尽管研究表明，IPF成纤维细胞表现出独特的病理表型，但知识的差距仍然存在较大的知识差距，而IPF肌纤维细胞的病理性质之间的差异仍然是促进性纤维化的，而肌纤维细胞的生理功能对于正常组织修复至关重要。考虑到这一点，包括该PPG的个别项目促进了一个统一的主题：直接提供对分子过程的洞察力，通过发现肌成纤维细胞细胞机制的组件使IPF成纤维细胞异常，从而导致IPF纤维化的纤维化以及在正常情况下恢复正常的纤维化。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，从而导致基本成纤维细胞细胞机械的病理变化稳定，可以在转录，翻译和信号转导的水平上识别。在此框架内，项目1（Henke）研究了整联蛋白 - 矩阵在调节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）评估了肌纤维细胞分化的转录控制。科学部分得到了行政核心（Henke）和生物测量和组织病理学核心（INGBAR）的支持。生物测量核心功能提供了每个研究者使用标准化的组织样品和细胞系，以减少细胞分离和培养过程中可能不受控制的成纤维细胞表型改变。因此，该计划项目聚集了一群具有不同专业知识领域的科学家，以共同的主题共同努力。该计划项目的一个主要目的是通过提供可以转化为IPF新型治疗策略的信息来为IPF临床网络的决策提供信息。