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.