TGF beta Receptors and Cell Proliferation

Project: Research project

Project Details

Description

? DESCRIPTION (provided by applicant): A central paradox in transforming growth factor beta (TGFß) 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 TGFß 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 TGFß 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 TGFß 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 TGFß signaling. As the number of effective therapeutic strategies for organ fibrosis is limited, delineating how metabolism interfaces with TGFß'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 TGFß 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 TGFß functions as a master switch during the process of fibrogenesis, but most importantly, directly impact the design and implementation of therapeutic strategies.
StatusNot started

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