Alternative Mechanisms of Adenosine Receptor Activation

腺苷受体激活的替代机制

• 批准号: 8064352
• 负责人: Holger K. Eltzschig
• 金额: $ 28.29万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064352
• 关键词: Acute; Address; Adenosine; Adenosine A1 Receptor; Adenosine A2B Receptor; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Area; Attenuated; Biological; Blood Vessels; Caco-2 Cells; Cells; Chronic; Colitis; Cyclic AMP; Data; Epithelial; Epithelium; Event; Gene Targeting; Genetic; Half-Life; Hypoxia; Hypoxia Inducible Factor; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Lead; Maintenance; Mass Spectrum Analysis; Metabolic; Metabolism; Modeling; Molecular; Molecular Weight; Mucositis; Mus; Myelogenous; Nucleoside Transporter; Oxygen; Pathway interactions; Patients; Play; Purinergic P1 Receptors; Receptor Signaling; Research; Research Design; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Surface; TNF gene; Testing; Therapeutic; Tissues; Transcriptional Regulation; Work; adenosine deaminase; adenosine receptor activation; attenuation; base; cytokine; defined contribution; design; expectation; extracellular; high throughput screening; human NTN1 protein; in vivo; in vivo Model; intestinal epithelium; migration; netrin receptor; netrin-1; neuronal guidance; novel; public health relevance; response; uptake

DESCRIPTION (provided by applicant): The large surface area covered by the intestinal epithelium is particularly prone to inflammation-associated hypoxia as may occur during inflammatory bowel disease. Here, extracellular adenosine signaling events play a major role in attenuating acute inflammation, particularly during conditions of limited oxygen availability. However, extracellular adenosine has an extremely short half-life on the epithelial surface of the intestine. This is due to rapid transport by nucleoside transporters and enzymatic metabolism. Therefore, we hypothesized the existence of endogenous non-adenosine-like compounds with biological activity on adenosine receptors (ARs). To pursue this hypothesis, we screened fractions derived from supernatants of hypoxic epithelia for AR activity. These studies found a single fraction with biological activity. Using mass spectrometry, we found that this fraction contained a dominant peak consistent with the mass of the neuronal guidance molecule netrin-1. Such studies revealed a surprising role for neuronal guidance molecule netrin-1 in alternative adenosine receptor activation and attenuation of mucosal inflammation during hypoxia. Based on these preliminary studies, it is our hypothesis that endogenous netrin-1 is released from hypoxic epithelia, and attenuates inflammatory hypoxia through AR-dependent signaling pathways. In the present proposal, we will further characterize the role of netrin-1 in alternative AR activation and its biological role in endogenous attenuation of mucosal inflammation as occurs during experimental colitis. PUBLIC HEALTH RELEVANCE: The present studies are designed to identify endogenous anti-inflammatory signaling pathways and to test these pathways in a therapeutic setting. This work will lay the groundwork for novel and specific therapeutic approaches in the treatment of mucosal inflammation, which are urgently needed - for example in the treatment of patients suffering from inflammatory bowel disease.

描述（由申请人提供）：肠上皮覆盖的大表面积特别容易发生与炎症相关的缺氧，这可能在炎症性肠病期间发生。在这里，细胞外腺苷信号传导事件在减轻急性炎症方面发挥着重要作用，特别是在氧气供应有限的情况下。然而，细胞外腺苷在肠上皮表面的半衰期极短。这是由于核苷转运蛋白和酶代谢的快速转运。因此，我们假设存在对腺苷受体（AR）具有生物活性的内源性非腺苷样化合物。为了验证这一假设，我们筛选了来自缺氧上皮细胞上清液的组分的 AR 活性。这些研究发现了具有生物活性的单一组分。使用质谱分析，我们发现该部分包含与神经元引导分子 netrin-1 的质量一致的主峰。此类研究揭示了神经元引导分子 netrin-1 在缺氧期间替代腺苷受体激活和粘膜炎症减弱中的惊人作用。基于这些初步研究，我们假设内源性 netrin-1 从缺氧上皮细胞中释放，并通过 AR 依赖性信号通路减轻炎症缺氧。在本提案中，我们将进一步描述 netrin-1 在选择性 AR 激活中的作用及其在实验性结肠炎期间发生的粘膜炎症内源性减弱中的生物学作用。 公共健康相关性：本研究旨在确定内源性抗炎信号通路并在治疗环境中测试这些通路。这项工作将为治疗粘膜炎症的新颖和具体的治疗方法奠定基础，例如治疗患有炎症性肠病的患者。