Profibrotic Role of TLR4 in Scleroderma: A Novel Target for Therapy

Project: Research project

Project Details

Description

Fibrosis, the hallmark of scleroderma, represents the transformation of normal wound-healing into a deregulated self-sustaining process thus contributing to high morbidity and mortality of this disease. While multiple intracellular signaling pathways are implicated in scleroderma fibrotic responses, the nature of their persistent deregulation in pathological inflammation and fibrosis remain poorly understood. Elucidation of the mechanism underlying the switch from self-limited repair to intractable scar is essential for designing rational therapies for scleroderma. Our recent studies demonstrated that an immune signaling receptor toll-like receptor4 (TLR4) and its endogenous ligand fibronectin-EDA and tenascin C are markedly elevated in scleroderma skin. Stimulation of TLR4 in fibroblasts was associated with the induction of extracellular matrix remodeling and tissue repair programs as well as synergistic enhancement of TGF-beta-mediated fibrotic responses. Thus, in a fibrogenic milieu enriched with TGF-beta and endogenous TLR4 ligands, fibroblasts expressing elevated TLR4 causes uncontrolled collagen synthesis and myofibroblast differentiation contributing to progression of fibrosis. Disrupting persistent TLR4 signaling with a novel small molecule TLR4 inhibitor with unique mechanism of action (by blocking ligand interaction to its receptor) represents a potential strategy for breaking the vicious cycle of progressive fibrosis in scleroderma. In this proposal, I will evaluate the effect of a novel small-molecule TLR4 inhibitor for anti-fibrotic efficacy in vivo in complementary mouse models of scleroderma using prevention and regression approaches, in ex vivo skin equivalent model mimicking scleroderma skin. To investigate the fibroblast-specific function of TLR4, I will generate mice with conditional TLR4 deletion in mesenchymal cells, and determine how TLR4 loss modulates the development of skin inflammation and fibrosis. Finally, I will derive a genome-wide TLR4 responsive gene signature by overexpressing constitutively active TLR4 in fibroblasts. This will be an important step for developing targeted anti-TLR4 therapy for scleroderma for identifying optimal responders likely to benefit in future clinical trials (beyond the scope of this proposal). As scleroderma has no approved viable therapy, and its multiple molecular subsets remain poorly understood, successful accomplishment of these goals comprising mechanistic and preclinical therapeutic approaches is expected to lead to rapid translation into clinical trials for scleroderma.
StatusFinished
Effective start/end date4/1/163/31/18

Funding

  • Scleroderma Foundation (Agreement 2/22/16)

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