title: Cellular mechanisms of tissue fibrosis. 8. Current and future drug targets in fibrosis: focus on Rho GTPase-regulated gene transcription.
abstract: Tissue fibrosis occurs with excessive extracellular matrix deposition from myofibroblasts, resulting in tissue scarring and inflammation. It is driven by multiple mediators, such as the G protein-coupled receptor ligands lysophosphatidic acid and endothelin, as well as signaling by transforming growth factor-β, connective tissue growth factor, and integrins. Fibrosis contributes to 45% of deaths in the developed world. As current therapeutic options for tissue fibrosis are limited and organ transplantation is the only effective treatment for end-stage disease, there is an imminent need for efficacious antifibrotic therapies. This review discusses the various molecular pathways involved in fibrosis. It highlights the Rho GTPase signaling pathway and its downstream gene transcription output through myocardin-related transcription factor and serum response factor as a convergence point for targeting this complex set of diseases.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan Scleroderma Program, Ann Arbor, Michigan;
authors.forename: Pei-Suen
authors.initials: PS
authors.lastname: Tsou
authors.affiliation: Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan; and.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Haak
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan Scleroderma Program, Ann Arbor, Michigan;
authors.forename: Dinesh
authors.initials: D
authors.lastname: Khanna
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan RNeubig@msu.edu.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
mesh_terms: D000818:Animals; D003240:Connective Tissue Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D006801:Humans; D058990:Molecular Targeted Therapy; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D026362:Serum Response Factor; D020741:rho GTP-Binding Proteins
keywords: Rho GTPase; drug development; fibrosis; gene transcription; therapeutics
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