Purinergic Modulation of Dermal Fibrosis

描述(由申请人提供)： 皮肤纤维化是系统性硬化症的一个标志。我们先前已经证明，在博莱霉素诱导的硬皮病小鼠模型中，刺激腺苷A2A受体可促进体外胶原的产生，而阻断腺苷A2A受体可减缓体内真皮纤维化的发展。这些发现与我们对肝纤维化模型的观察同时进行，在肝纤维化模型中，腺苷A2a受体拮抗剂延缓了化学诱导的小鼠肝硬化。我们最近发现，在高组织腺苷(腺苷脱氨酶缺乏症)小鼠模型中，致纤维化细胞因子IL-13的水平在皮肤中升高。为了更好地了解腺苷A2a受体拮抗剂对硬皮病真皮纤维化的保护作用机制，我们将研究：1腺苷对真皮成纤维细胞IL-13反应性的影响；2腺苷和IL-13对FLI1功能的影响；3腺苷对CCN2的作用。最终，我们希望这些研究将允许我们考虑使用小分子，如腺苷受体拮抗剂来治疗硬皮病的皮肤纤维化。 公共卫生相关性： 叙述失控和过度的纤维组织形成可能导致弥漫性皮肤和器官纤维化，如硬皮病。本文提出的研究旨在进一步证实腺苷及其受体在促进皮肤纤维化中的作用，以及腺苷受体刺激组织基质产生的机制。更好地了解腺苷及其受体在真皮纤维化中的作用，有助于开发新的药物来预防或改善以硬皮病为特征的皮肤纤维化，目前尚无有效的治疗方法。

DESCRIPTION (provided by applicant): Dermal fibrosis is a hallmark of systemic sclerosis. We have previously demonstrated that stimulation of adenosine A2A receptor promotes collagen production in vitro while blockade of the adenosine A2A receptor attenuates development of dermal fibrosis in vivo in a bleomycin-induced murine model of scleroderma. These findings parallel our observations on models of hepatic fibrosis where adenosine A2A receptor antagonists retard chemically-induced murine cirrhosis. We have recently shown that levels of the fibrogenic cytokine, IL-13 are elevated in the skin in a murine model of high tissue adenosine (adenosine deaminase deficiency). Furthermore, an A2A receptor antagonist reverses the IL-13 increase and decreases message for IL-13 receptor 1. To better understand the mechanisms by which adenosine A2A receptor antagonism protects against dermal fibrogenesis in scleroderma, we will study: Specific Aim 1 The effect of adenosine on IL-13 responsiveness in dermal fibroblasts Specific Aim 2 The effect of adenosine and IL-13 on Fli1 function Specific Aim 3 The effect of adenosine on CCN2. Ultimately, we hope that these studies will allow us to consider the use of small molecules such as adenosine receptor antagonists in the therapy of dermal fibrosis in scleroderma. PUBLIC HEALTH RELEVANCE: NARRATIVE Uncontrolled and excessive fibrous tissue formation may result in diffuse skin and organ fibrosis such as that seen in scleroderma. The studies proposed herein are designed to further confirm the role of adenosine and its receptors in promoting fibrosis in the skin as well as the mechanisms by which adenosine receptors stimulate tissue matrix production. A better understanding of the role of adenosine and its receptors in dermal fibrosis could facilitate the development of new agents that prevent or ameliorate the skin fibrosis that characterizes scleroderma, for which no effective treatment exists at present.