The Pharmacology of Dermal Fibrosis

真皮纤维化的药理学

• 批准号: 8698898
• 负责人: BRUCE Neil CRONSTEIN
• 金额: $ 31.65万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-11-14 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698898
• 关键词: 5' -Nucleotidase; Adenosine; Adenosine A2A Receptor; Adenosine A2B Receptor; Animal Model; Animals; Bleomycin; Cell physiology; Cells; Cicatrix; Clinic; Collagen; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dermal; Development; Diffuse; Diffuse Scleroderma; Disease; Experimental Models; Fibroblasts; Fibrosis; Future; Genetic Transcription; Growth Factor; Hepatic Stellate Cell; Hypertrophic Cicatrix; Hypoxia; In Vitro; Interferons; Keloid; Knockout Mice; Laboratories; Lead; Life; Liver Cirrhosis; Liver Fibrosis; MAPK14 gene; Mediating; Medical; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; New Agents; Nuclear; Organ; Pathologic; Pathway interactions; Pharmacology; Platelet-Derived Growth Factor; Play; Process; Production; Pulmonary Fibrosis; Purine Nucleosides; Purinergic P1 Receptors; Radiation Pneumonitis; Regulation; Reporting; Research Design; Role; Scleroderma; Signal Pathway; Signal Transduction; Skin; Small Interfering RNA; TNF gene; Techniques; Tendon structure; Thioacetamide; Tissues; Toxin; Wound Healing; adenosine deaminase; connective tissue growth factor; cytokine; extracellular; fibrosing agent; in vivo; interleukin-13 receptor; mortality; nucleoside triphosphate; prevent; pyrophosphatase; receptor; receptor expression; receptor function; repaired; research study; small molecule; src-Family Kinases; therapy development; tissue repair

Matrix replacement and repair is required for wound healing but when the process is overly exuberant, as in scar or keloid formation, or when it occurs inappropriately, as in Scleroderma and other fibrosing diseases, it can lead to morbidity and, in the case of Scleroderma, mortality. Although it is clear that growth factors play a central role in fibrosis the role of small molecules in pathologic fibrosis has not been well explored. We have recently demonstrated that the purine nucleoside adenosine, acting through the adenosine A2A receptor, plays a central role in the fibrosis that develops in experimental models of hepatic cirrhosis and scleroderma. We propose here to further determine whether adenosine and adenosine receptors play a role in pathologic fibrosis and to dissect the molecular mechanism by which adenosine A2A receptors on fibroblasts stimulate overproduction of collagen and other matrix constituents. To this end we have proposed to study: I. The role of adenosine receptors in pathologic fibrosis We will study the development of hypertrophic scarring in a model of dermal scarring and diffuse dermal fibrosis induced by bleomycin treatment in wild type, adenosine A1, A2A, A2B and A3 receptor knockout mice, mice that generate less extracellular adenosine (ecto‐5’Nucleotidase and nucleoside triphosphate pyrophosphatase knockout mice) and mice treated with adenosine receptor antagonists; II. Signaling at adenosine A2A receptors for fibrosis In preliminary experiments we have observed that adenosine A2A receptor stimulation diminishes nuclear fli1 levels, a constitutive repressor of CTGF expression, a change which may mediate the profibrotic effects of adenosine and the A2A receptor. We will dissect the signaling pathways from adenosine A2A receptors to suppression of fli1 expression and nuclear localization using a combination of pharmacologic and siRNA‐mediated knockdown techniques; III. Cross‐talk between adenosine A2A receptors and receptors for “anti‐fibrotic” cytokines We have previously demonstrated that interferon‐γ, an anti‐fibrotic cytokine, diminishes adenosine A2A receptor expression and, more dramatically, function. We will study the mechanism by which interferon‐γ downregulates adenosine A2A receptor function with a combination of pharmacologic and molecular (siRNA‐mediated knockdown) methods. In future experiments we will examine the role of adenosine receptors in keloid formation and other clinicallyrelevant forms of pathologic fibrosis (e.g. radiation fibrosis). Because adenosine receptor antagonists are under development for the treatment of a variety of medical conditions it may be possible to quickly bring the information garnered in these studies to the clinic.

基质更换和修复是伤口愈合所必需的，但当过程过度时 旺盛的，旺盛的，如在疤痕或瘢痕疙瘩形成中，或当它发生不当时，如硬皮病 以及其他纤维性疾病，它会导致发病率，就硬皮病而言，还会导致死亡。 尽管很明显，生长因子在纤维化中起着中心作用，但小分子的作用 在病理性纤维化方面还没有得到很好的探讨。我们最近已经证明了 嘌呤核苷腺苷通过腺苷A2a受体发挥作用，在 在实验性的肝硬变和硬皮病模型中发展起来的纤维化。我们 建议进一步确定腺苷和腺苷受体是否在 病理纤维化及腺苷A2a受体的分子机制 对成纤维细胞刺激胶原和其他基质成分的过度产生。为此， 我们建议研究：1.腺苷受体在病理性纤维化中的作用 在真皮瘢痕和弥漫性瘢痕模型中研究增生性瘢痕的发展 博莱霉素处理野生型、腺苷A1、A2A、A2B和A3诱导的真皮纤维化 受体基因敲除小鼠，产生较少胞外腺苷(ecto-5‘核苷酸酶)的小鼠 和核苷三磷酸焦磷酸酶基因敲除小鼠)和腺苷处理的小鼠 受体拮抗剂；II.腺苷A2a受体信号转导与纤维化的初步研究 我们已经观察到腺苷A2a受体的刺激减少了核内的FLI1 水平，CTGF表达的结构性抑制因子，这一变化可能介导了纤维前病变 腺苷和A2a受体的作用。我们将从以下几个方面剖析信号通路 腺苷A2a受体抑制FlI1表达及核定位的研究 药理学和siRNA介导的击倒技术的组合；III.串扰 在腺苷A2a受体和“抗纤维化”细胞因子受体之间 先前证明，干扰素-γ，一种抗纤维化细胞因子，减少腺苷A2a 受体的表达，以及更戏剧性的功能。我们将研究通过什么机制 干扰素-γ联合应用下调腺苷A2a受体功能 药理学和分子(siRNA介导的基因敲除)方法。在未来的实验中 我们将研究腺苷受体在瘢痕疙瘩形成和其他临床相关因素中的作用。 病理性纤维化的形式(如放射性纤维化)。因为腺苷受体 拮抗剂正在开发中，用于治疗它可能出现的各种医疗状况 有可能迅速将在这些研究中获得的信息带到临床上。