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The Pharmacology of Dermal Fibrosis

真皮纤维化的药理学

基本信息

批准号：
8891056
负责人：
BRUCE Neil CRONSTEIN
金额：
$ 37.29万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8891056
关键词：
ADORA2A gene Adenine Nucleotides Adenosine Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Antiviral Agents Bleomycin Cell Nucleus Cessation of life Chronic Cicatrix Collagen Cyclic AMP Cyclic AMP-Dependent Protein Kinases Dermal Development Diffuse Disease Dose-Limiting Enzymes Epithelial Extracellular Space Fibroblasts Fibrosis Growth Factor HIV HIV Infections Hepatitis B Hepatitis B virus Pol Protein Hyperplasia Hypoxia In Vitro Infiltration Inflammation Injury Interferons Investigation Knock-out Knockout Mice Lead Light Limb structure Liver Liver Cirrhosis Liver Fibrosis Lymphocyte Malignant Neoplasms Measures Modeling Mus Nuclear Translocation Organ Pathogenesis Pattern Pharmacology Phosphoric Monoester Hydrolases Platelet-Derived Growth Factor Play Prevention Prevention approach Process Production Purine Nucleosides RNA-Directed DNA Polymerase Radiation Radiation Injuries Radiation Pneumonitis Radiodermatitis Receptor Signaling Role Scleroderma Signal Pathway Signal Transduction Site Skin Tenofovir Testing Therapeutic Thick Tissues Toxic effect Transforming Growth Factor beta Translating Trauma Wild Type Mouse Wound Healing analog beta catenin cell type connective tissue growth factor cytokine efficacy testing extracellular in vivo irradiation keratinocyte loss of function novel novel strategies prevent programs public health relevance receptor receptor function research study skin disorder therapy design tissue regeneration

项目摘要

DESCRIPTION (provided by applicant): 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/ß-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 ß-catenin activation and translocation to the nucleus and whether A2AR promotion of collagen synthesis depends on ß-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.

描述（由申请人提供）：皮肤纤维化可能由多种损伤引起，包括创伤、辐射或硬皮病等疾病。纤维化不仅会毁容，它还可能导致由于功能丧失和内脏纤维化而导致的死亡，如硬皮病或肝硬化所发生的。在该项目的初始阶段进行的初步研究中，我们已经部分阐明了腺苷在刺激胶原蛋白产生中作用于A2 A受体（A2 AR）的作用，胞外酶在纤维化部位产生腺苷的作用以及A2 AR阻断剂在动物模型中减少瘢痕形成的能力。在初步研究中，我们发现替诺福韦，一种AMP类似物，抑制HIV逆转录酶和B型肝炎病毒聚合酶，降低细胞外腺苷水平，减少硬皮病和肝硬化小鼠模型中的纤维化。在其他研究中，我们发现A2 AR阻断减少了放射性皮炎和纤维化，并且A2 AR刺激通过与Wnt/β-连环蛋白信号通路的串扰促进胶原蛋白的产生。我们在这里提出了一个高度转化的研究计划，以间接和直接靶向A2 AR治疗和预防纤维化的潜在治疗效用，并确定参与A2 AR刺激胶原蛋白产生的信号传导机制。我们提出以下三个目标：一。确定替诺福韦（一种AMP类似物，可抑制HIV逆转录酶和B型肝炎病毒聚合酶）预防皮肤和肝脏纤维化的机制。我们将在小鼠模型中测试替诺福韦对皮肤和肝纤维化的影响，确定替诺福韦是否通过阻断腺嘌呤核苷酸经由泛连接蛋白1释放或细胞外腺嘌呤核苷酸转化为腺苷来降低细胞外腺苷水平; II.研究A2 AR阻断和缺失对辐射诱导的纤维化、上皮增生和炎症的影响。我们将确定局部A2 AR阻断或A2 AR缺失是否在鼠模型中局部皮肤照射后防止皮肤纤维化、增加的上皮增殖和淋巴细胞浸润; III.我们将剖析A2 AR和Wnt信号之间的串扰。我们将确定A2 AR刺激对β-连环蛋白活化和核转位的影响，以及A2 AR促进胶原合成是否依赖于体外和体内β-连环蛋白活化和核转位。我们还将研究A2 AR刺激的成纤维细胞和角质形成细胞中的表达模式。拟议实验的结果将为纤维化疾病的治疗和预防提供新的靶点，并阐明纤维化相关的信号通路。