Understanding the Role of TGF-b1 in Interstitial Lung Disease Using A Multi-Scale Systems Biology Approach

[摘要] Pulmonary diseases are a major global health burden affecting approximately one billion people every year. They result from many types of insults including but not limited to infections, such as tuberculosis (TB), and dysregulations of the lung physiology, such as idiopathic pulmonary fibrosis. (IPF) The key to producing better therapeutics to treat pulmonary diseases is in understanding the role of immune mediators in these diseases. Transforming growth factor-β1 (TGF-β1) is an immune mediator that has been implicated in the exacerbation of both TB and IPF. TGF-β1 is traditionally described as and anti-inflammatory cytokine, thought to restrict the immune response. TGF-β1 affects a variety of cellular processes including proliferation, cytokine secretion, and even apoptosis. These effects are very cell type specific and often concentration dependent. Effective modulation of the immune response through TGF-β1 requires understanding which cells are being regulated, what are the specific results of TGF-β1 regulation, and through what mechanisms TGF-β1 is acting on the cells. To answer these questions it is necessary to look across biological scales at TGF-β1 signaling on a molecular scale, a cellular scale, and a tissue scale.The role of TGF-β1 across multiple biologic scales has not been well characterized in the context of pulmonary disease. In this work I took a multi-scale systems biology approach to understanding the mechanistic role of TGF-β1 in pulmonary disease across molecular, cellular, and tissue scales. I constructed a novel ordinary differential equation (ODE) model of TGF-β1 receptor ligand signaling in a single fibroblast and from that model, identified the necessity forsimultaneous TGF-β1 and prostaglandin E2 signaling to maintain homeostatic fibroblast response during injury. I then combined this ODE model with a novel in silico agent based model (ABM) of fibroblasts and epithelial cells in co-culture in order to evaluate the effects of molecular scale signaling dynamics of cellular scale outputs such as cell proliferation, differentiation, and survival. With this model I identified a need for differential therapeutic treatment of fibroblasts and epithelial cells in order to prevent exacerbation of fibrotic disease.I then introduced TGF-β1 signaling into the existing in silico ABM model of TB induced granuloma formation in the lung (GranSim). Using this updated version of GranSim in combination with studies performed in non-human primates, I demonstrate the inhibition of TGF-β1 in the granuloma increases bacterial killing and promotes lesion sterilization by enabling increased effector functions from cytotoxic T cells. I also show that macrophages and cytotoxic T cells are differentially regulated in the granuloma by interleukin-10 and TGF-β1 respectively.Finally, I combine work on fibrosis and granuloma formation by introducing fibroblasts with an ODE model defining TGF-β1 receptor-ligand signaling dynamics into GranSim in order to characterize the formation of fibrotic granulomas. In this work I have advanced the understanding of TGF-β1 regulation in pulmonary disease and opened doors for further examination of potential therapeutic targets to treat these diseases.

[发布机构] University of Michigan

[效力级别] Microbiology and Immunology

[关键词] Transforming growth factor-beta;Microbiology and Immunology;Science;Microbiology & Immunology