HL-Role of c-Myc in myofibroblast differentiation in pulmonary fibrosis

Project: Research project

Project Details

Description

? DESCRIPTION (provided by applicant): HL-131: Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive, and ultimately fatal disorder with a poorly understood pathogenesis and no cure. Patients with IPF typically survive 2 to 4 years after diagnosis. IPF is associated with the progressive invasion of the lung parenchyma by activated mesenchymal cells, in particular myofibroblasts, which form `fibroblastic foci' and cause scarring by depositing excessive extracellular matrix resulting in a loss of alveolar architecture. The goal of this proposal is to identify the mesenchymal cell type that gives rise to myofibroblasts and its mechanism of differentiation. Our preliminary studies show that lipofibroblasts are the source for the majority of myofibroblasts after bleomycin injury. In addition, our data indicate that during te resolution phase a subset of myofibroblasts revert back to the lipofibroblast lineage. Our preliminary data also demonstrate that c-Myc, a key Wnt target gene in lung mesenchyme, is strongly expressed in myofibroblasts in lungs after bleomycin injury. Interestingly, our preliminary data also indicate that overexpression of c-Myc by itself (in the absence of lung injury) is sufficient to drive the differentiation and accumulation of myofibroblasts throughout th lung parenchyma. These myofibroblasts are highly proliferative and express high levels of c-Myc, ?-Sma and collagen compared to surrounding or wild type mesenchyme. We hypothesize that c-Myc induces lipofibroblast to myofibroblast transdifferentiation and their subsequent proliferation in pulmonary fibrosis. We also hypothesize that c-Myc inactivation in myofibroblasts will promote the resolution of fibrotic lung disease by promoting dedifferentiation of myofibroblasts into non proliferative lipofibroblasts. These hypotheses will be addressed with three specific aims. In specific aim 1 we will test the hypothesis that lipofibroblasts transdifferentiate into myofibroblasts after bleomycin-mediated lung injury and that myofibroblasts dedifferentiate into lipofibroblasts during the resolution of fibrosis in mice. In specific aim 2 we will test the hypothesis that c-Myc is sufficient to transdifferentiate lipofibroblasts into highly proliferative myofibroblasts and to maintain their differentiation stats. Lastly in specific aim 3 we will test the hypothesis that c-Myc in lipofibroblasts is necessary for the development, proliferation and maintenance of myofibroblasts after bleomycin-mediated lung injury. From a therapeutic point of view, the control of the differentiation status of the myofibroblasts is almost completely unexplored. The proposed studies should significantly advance our knowledge of pulmonary fibrosis: (i) by identifying the origin of the cells that give rise to myofibroblasts in pulmonary fibrosis; (ii) by validating the concept of manipulating lipofibroblast to myofibroblast transdifferentiation as well as the reverse process as an intriguin new therapeutic option for the treatment of fibroproliferative lung diseases; (iii) by identifying -Myc as the main driver of LIF to MYF transdifferentiation and their subsequent proliferation, and as such validating c-Myc as a potential therapeutic target to treat pulmonary fibrosis.
StatusFinished
Effective start/end date4/1/154/30/20

Funding

  • National Heart, Lung, and Blood Institute: $425,537.00
  • National Heart, Lung, and Blood Institute: $437,662.00
  • National Heart, Lung, and Blood Institute: $472,148.00
  • National Heart, Lung, and Blood Institute: $472,148.00

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