Dermal fibrosis may result from a variety of insults including trauma, irradiation or such diseases as scleroderma. Not only is fibrosis disfiguring but it may also lead to death due to loss of function and fibrosis of internal organs, as occurs in scleroderma or cirrhosis of the liver. In preliminary studies carried out during the initial term o this project we have elucidated, in part, the role of adenosine, acting at A2A receptors (A2AR) in stimulating collagen production, the role of ecto-enzymes in producing adenosine at fibrotic sites and the capacity of A2AR blockade to diminish scarring in an animal model. In preliminary studies we have discovered that tenofovir, an AMP analogue that inhibits HIV reverse transcriptase and Hepatitis B Virus polymerase, reduces extracellular adenosine levels and diminishes fibrosis in murine models of scleroderma and hepatic cirrhosis. In other studies we have found that A2AR blockade diminishes radiation dermatitis and fibrosis and that A2AR stimulation promotes collagen production via cross-talk with Wnt/-catenin signaling pathways. We propose here a highly translational program of investigation into the potential therapeutic utility of indirectly and directly targeting A2AR to treat and prevent fibrosis and to determine th signaling mechanisms involved in A2AR stimulation of collagen production. We propose the following three aims: I. Determine the mechanism by which tenofovir, an AMP analogue that inhibits HIV reverse transcriptase and Hepatitis B Virus polymerase, prevents fibrosis in the skin and liver. We will test the effect of tenofovir on dermal and hepatic fibrosis in murine models and determine whether tenofovir diminishes extracellular adenosine levels by blocking adenine nucleotide release via pannexin 1 or conversion of extracellular adenine nucleotides to adenosine; II. To examine the effect of A2AR blockade and deletion on radiation-induced fibrosis, epithelial hyperplasia and inflammation. We will determine whether topical A2AR blockade or A2AR deletion prevents dermal fibrosis, increased epithelial proliferation and infiltration with lymphocytes following localized dermal irradiation in a murine model; III. We wil dissect cross-talk between A2AR and Wnt signaling. We will determine the effect of A2AR stimulation on -catenin activation and translocation to the nucleus and whether A2AR promotion of collagen synthesis depends on -catenin activation and nuclear translocation both in vitro and in vivo. We will also examine expression patterns in A2AR-stimulated fibroblasts and keratinocytes. The results of the proposed experiments will provide novel targets for the treatment and prevention of fibrosing conditions and shed light on signaling pathways involved in fibrosis.
Fibrosis and scarring result, in the skin, from injury or a variety of diseases and can lead not only to disfigurement but also to diminished function of the affected limb. Despite recent advances in our understanding of how cellular production of collagen, the principal component of fibrous tissue, is regulated we have yet to come up with an effective approach to prevention or treatment of fibrosing diseases of the skin or internal organs. Here we propose to test the efficacy of therapies designed to diminish extracellular adenosine or block adenosine A2A receptors on the development of fibrosis and to better understand how adenosine A2A receptors stimulate collagen production.
|Mediero, Aránzazu; Wilder, Tuere; Shah, Lopa et al. (2018) Adenosine A2A receptor (A2AR) stimulation modulates expression of semaphorins 4D and 3A, regulators of bone homeostasis. FASEB J 32:3487-3501|
|Haskó, György; Antonioli, Luca; Cronstein, Bruce N (2018) Adenosine metabolism, immunity and joint health. Biochem Pharmacol 151:307-313|
|Yang, Lu; Fanok, Melania H; Mediero-Munoz, Aranzazu et al. (2018) Augmented Th17 Differentiation Leads to Cutaneous and Synovio-Entheseal Inflammation in a Novel Model of Psoriatic Arthritis. Arthritis Rheumatol 70:855-867|
|Cronstein, Bruce N; Sitkovsky, Michail (2017) Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nat Rev Rheumatol 13:41-51|
|Corciulo, Carmen; Lendhey, Matin; Wilder, Tuere et al. (2017) Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression. Nat Commun 8:15019|
|Ishack, Stephanie; Mediero, Aranzazu; Wilder, Tuere et al. (2017) Bone regeneration in critical bone defects using three-dimensionally printed ?-tricalcium phosphate/hydroxyapatite scaffolds is enhanced by coating scaffolds with either dipyridamole or BMP-2. J Biomed Mater Res B Appl Biomater 105:366-375|
|Feig, Jessica L; Mediero, Aranzazu; Corciulo, Carmen et al. (2017) The antiviral drug tenofovir, an inhibitor of Pannexin-1-mediated ATP release, prevents liver and skin fibrosis by downregulating adenosine levels in the liver and skin. PLoS One 12:e0188135|
|Zhang, Jin; Corciulo, Carmen; Liu, Hailing et al. (2017) Adenosine A2a Receptor Blockade Diminishes Wnt/?-Catenin Signaling in a Murine Model of Bleomycin-Induced Dermal Fibrosis. Am J Pathol 187:1935-1944|
|Bradaschia-Correa, Vivian; Josephson, Anne M; Egol, Alexander J et al. (2017) Ecto-5'-nucleotidase (CD73) regulates bone formation and remodeling during intramembranous bone repair in aging mice. Tissue Cell 49:545-551|
|Mediero, Aránzazu; Wilder, Tuere; Ramkhelawon, Bhama et al. (2016) Netrin-1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis. FASEB J 30:3835-3844|
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