Metabolic Regulation of Myofibroblast Differentiation

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Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease which has a median survival of 3.5 years and affects approximately 89,000 people in the United States. There is no known genetic cause of IPF, and thus identification of new mechanisms required for disease pathogenesis is of critical importance for the development of novel treatment strategies. A defining feature of IPF is the differentiation of lung fibroblasts into myofibroblasts, which secrete excessive amounts of extracellular matrix (collagen) and are the primary cell responsible for the structural remodeling and impairment of lung function characteristic of IPF. We have recently discovered that myofibroblasts depend on metabolic reprogramming characterized by increased levels of glycolysis and metabolite flux through the de novo serine, glycine, one-carbon (SGOC) pathway to promote glycine production for collagen protein synthesis. Glycine constitutes one third of all amino acids in collagen protein and de novo synthesis of glycine from glucose is required to support collagen protein synthesis by myofibroblasts. However, the signaling and transcriptional regulators of this metabolic reprogramming in fibroblasts are unknown. The central goal of this proposal is to identify the regulators of metabolic reprogramming in myofibroblasts and to determine their role in lung fibrosis. The premise underlying this goal is that elucidating the mechanisms of metabolic regulation in myofibroblasts will unveil new strategies to fulfill the sorely unmet therapeutic need in IPF. Our preliminary results show that TGF-β (Transforming Growth Factor-β, the key cytokine involved in fibrosis), promotes signaling through the mTOR pathway, which activates ATF4 (activating transcription factor 4). ATF4 is required for the expression of SGOC pathway enzymes in myofibroblasts. We further show that SGOC pathway activation not only promotes collagen protein production by myofibroblasts, but alters the epigenome of these cells, possibly providing additional ways to target myofibroblast biology for therapeutic purposes. In the current proposal, we aim to determine the regulators of myofibroblast metabolism and determine the mechanisms by which altered metabolism contributes to the myofibroblastic phenotype. In Specific Aim 1 we will determine how the transcription factor ATF4 regulates the SGOC and other metabolic pathways in lung fibroblasts in vitro and in vivo. In Specific Aim 2, we will determine how the mTOR signaling pathway regulates ATF4 and other transcriptional regulators of cellular metabolism in lung fibroblasts in vitro and in vivo. In Specific Aim 3, we will determine how SGOC pathway activation contributes to epigenetic changes in lung fibroblasts in vitro and in vivo. Our proposed experiments will identify and fully characterize multiple targetable pathways required for fibrogenesis.