Purinergic Modulation of Dermal Fibrosis

真皮纤维化的嘌呤能调节

• 批准号: 7928952
• 负责人: EDWIN SL CHAN
• 金额: $ 8.45万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-09 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7928952
• 关键词: Adenosine; Adenosine A2A Receptor; Affect; Attenuated; Bleomycin; Cirrhosis; Collagen; Collagen Gene; Dermal; Development; Diffuse; Fibroblasts; Fibrosis; Gene Expression; In Vitro; Interleukin-13; Liver Fibrosis; Mediating; Modeling; Mus; New Agents; Organ; Production; Proteins; Purinergic P1 Receptors; Role; Scleroderma; Skin; Stimulus; Systemic Scleroderma; Tissues; adenosine deaminase deficiency; connective tissue growth factor; cytokine; design; effective therapy; fibrogenesis; in vivo; interleukin-13 receptor; prevent; public health relevance; receptor; response; small molecule

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.

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