A central paradox in transforming growth factor beta (TGF) biology is how the same growth factor can induce such divergent responses as growth stimulation (i.e., mesenchymal cells) and growth inhibition (i.e., epithelial cells)? Considering te pivotal role TGF has in a number of normal and pathological conditions, addressing that issue is fundamental if we hope to develop specific intervention strategies. To that end, we propose to test the general hypothesis that profibrotic TGF signaling reflects the coordinate action of metabolic dysregulation with the induction of proliferative and antiapoptotic cytokines. In support of that proposal, evidence is provided that (i) fatty acid synthase (FASN) and hexokinase 2 (HK2) represent novel targets integrating the fibroproliferative action of TGF with metabolic regulation; and (ii) the insulin-like growth factor 1 (IGF-1) axis (i.e., includes ligand and bindig proteins) represents a cell type-specific module promoting cell survival and the myofibroblast phenotype. In this competing renewal we will extend these concepts both in vitro and in vivo using a variety of biochemical, genetic, and morphologic approaches. First, we will define the role of a metabolic regulatory network in profibrotic TGF signaling. As the number of effective therapeutic strategies for organ fibrosis is limited, delineating how metabolism interfaces with TGF's fibroproliferative actions has the potential to completely modify the manner by which fibrotic diseases are treated. Second, the mechanism(s) of cell type-specific IGF-1 induction by TGF as well as the ability by which inhibiting IGF-1 signaling chemosensitizes fibrotic foci to metabolic stress will be defined. These results not only expand the paradigm through which TGF functions as a master switch during the process of fibrogenesis, but most importantly, directly impact the design and implementation of therapeutic strategies.
TGF is a protein which can be either helpful or harmful to human health. While its ability to stimulate cell growth is important for normal wound healing, when unchecked the function of many organs can be disrupted by scar (i.e., fibrosis) formation. Conversely, the growth inhibitory actions of TGF are critical in preventing cancer. The proposed studies will identify/characterize targets which direct these different activities and can be used to either increase or decrease the response.
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