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 contractions and loss of function and fibrosis of internal organs, as occurs in scleroderma or cirrhosis of the liver, can be lethal. In preliminary studies carried out during the initial term of this project we have elucidated, in part, the role of adenosine, acting at the A2A receptor (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 Hepatithis 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 the 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 fibrosisin 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. The results of the proposed experiments will provide novel targets for therapeutic development in the treatment and prevention of fibrosing conditions and shed light on the signaling pathways involved in pathologic fibrosing conditions.
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 further 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.
|Perez-Aso, Miguel; Mediero, ArÃ¡nzazu; Low, Yee Cheng et al. (2016) Adenosine A2A receptor plays an important role in radiation-induced dermal injury. FASEB J 30:457-65|
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|Mediero, ArÃ¡nzazu; 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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|Mediero, ArÃ¡nzazu; Ramkhelawon, Bhama; Perez-Aso, Miguel et al. (2015) Netrin-1 is a critical autocrine/paracrine factor for osteoclast differentiation. J Bone Miner Res 30:837-54|
|Perez-Aso, Miguel; Montesinos, M Carmen; Mediero, ArÃ¡nzazu et al. (2015) Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors. Arthritis Res Ther 17:249|
|Montesinos, M Carmen; Desai-Merchant, Avani; Cronstein, Bruce N (2015) Promotion of Wound Healing by an Agonist of Adenosine A2A Receptor Is Dependent on Tissue Plasminogen Activator. Inflammation 38:2036-41|
|Goodman, Susan M; Cronstein, Bruce N; Bykerk, Vivian P (2015) Outcomes related to methotrexate dose and route of administration in patients with rheumatoid arthritis: a systematic literature review. Clin Exp Rheumatol 33:272-8|
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