Identifying key mechanisms in fibroblast disregulation using a systems biology approach. (IRM9P.727)

Pulmonary fibrosis, stiffening and scarring of the lung tissue, is a symptom of interstitial lung disease with no available treatments and poor prognosis for patients. It occurs when disregulation of the proliferative and remodeling phases of the wound healing process results in uncontrolled proliferation and activation of fibroblasts, excessive extracellular matrix deposition, and detrimental tissue remodeling. The molecular mechanisms underlying this disregulation are poorly understood providing an untapped pool of potential therapeutic targets. TGFβ is known to be an important factor in fibroblast activation while Pge2 has been shown to counteract TGFβ; however the mechanistic details of this relationship have not been characterized. To this end, we combined computation and experimental techniques to study these cellular and molecular scale events. In vitro experiments are done in parallel with computation experiments and used to build and validate an in silico model. We created a hybrid multi-scale model focusing on the roles of TGFβ receptor ligand signaling dynamics with downstream signaling events leading to fibroblast activation, and fibroblast and epithelial cell co-regulation. Analysis of our model allows evaluation of real-time molecular events in the context of a simultaneous fibroblast/epithelial cell co-culture system. With these tools we have identified key factors driving fibroblast regulation and predict potential therapeutic targets for pulmonary fibrosis.