Mechanisms of Adenosine Protection

腺苷保护机制

• 批准号: 8475473
• 负责人: Sean P Colgan
• 金额: $ 32.42万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8475473
• 关键词: 5' -Nucleotidase; Adenosine; Anti-Inflammatory Agents; Anti-inflammatory; Biological Markers; Cell Line; Cells; Colitis; Cullin 2 Protein; Cullin Proteins; Data; Disease; Disease Outcome; Enzymes; Epithelial; Epithelial Cells; Epithelium; Event; Family; FarGo; Foundations; Generations; Genotype; Hypoxia; Hypoxia Inducible Factor; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Learning; Mediating; Metabolic; Metabolism; Modeling; Molecular; Molecular Target; Motion; Mucositis; Mucous Membrane; Mus; Nucleotides; Oxygen; Pathway interactions; Patients; Positioning Attribute; Process; Production; Protein Family; Publishing; Purinergic P1 Receptors; Regulation; Role; Series; Signal Transduction; Site; Staging; Surface; System; Testing; Tissues; Ubiquitin; Work; base; cell type; defined contribution; extracellular; feeding; in vivo; in vivo Model; inhibitor/antagonist; neutrophil; novel; novel therapeutic intervention; research study; response; therapeutic target; ubiquitin ligase

DESCRIPTION (provided by applicant): Inflammation is accompanied by a substantial shift in tissue metabolism. One of the major metabolic signatures of inflammation is hypoxia, which is recently appreciated to significantly influence inflammatory disease outcome. Early in the disease process, such "inflammatory hypoxia" results, in large extent, from the recruitment of oxygen demanding inflammatory cell types, particularly neutrophils. In recent years, we have focused on defining targets and molecular pathways set into motion by inflammatory hypoxia. Results from these studies have defined a series of novel signaling mechanisms in which hypoxia (both in vitro and in vivo) drives the metabolism of extracellular nucleotides toward the generation of large amounts of extracellular adenosine. Central to this pathway was the identification of hypoxia-inducible factor (HIF) as an important regulator of the enzymes necessary for Ado metabolism (esp. CD73), thus identifying HIF-regulated Ado production as an endogenous anti-inflammatory pathway. Ongoing studies have revealed that Ado regulates HIF through the active deneddylation of Cullins, a family of proteins critical for the recruitment of ubiquitin ligases. Based on these preliminary studies, we hypothesize that Ado generated early in the inflammatory response functions as a feed-forward anti- inflammatory mechanism through direct actions on mucosal HIF stabilization. Three specific aims are directed at testing this hypothesis: In Specific Aim 1, we will define the contribution of neutrophils and epithelia to Ado generation at sites of inflammation. Specific Aim 2 will extend preliminary data to elucidate mechanisms of Ado-mediated Cullin-2 de-neddylation. Specific Aim 3 will Probe the role of Ado to HIF-mediated protection. The overall aim of this proposal is to identify novel metabolic signaling by HIF and Ado within the mucosa during inflammatory hypoxia.

描述（由申请人提供）：炎症伴随着组织代谢的显着变化。炎症的主要代谢特征之一是缺氧，最近人们认识到缺氧可显着影响炎症性疾病的结果。在疾病过程的早期，这种“炎症性缺氧”在很大程度上是由需氧炎症细胞类型（尤其是中性粒细胞）的募集造成的。近年来，我们重点关注确定炎症性缺氧启动的靶点和分子途径。这些研究的结果定义了一系列新的信号传导机制，其中缺氧（体外和体内）驱动细胞外核苷酸的代谢，产生大量细胞外腺苷。该途径的核心是缺氧诱导因子 (HIF) 被鉴定为 Ado 代谢所需酶（尤其是 CD73）的重要调节剂，从而将 HIF 调节的 Ado 产生鉴定为内源性抗炎途径。正在进行的研究表明，Ado 通过 Cullins 的活性去甲基化来调节 HIF，Cullins 是一个对泛素连接酶的招募至关重要的蛋白质家族。基于这些初步研究，我们假设 Ado 在炎症反应早期产生，通过直接作用于粘膜 HIF 稳定作用，发挥前馈抗炎机制的作用。三个具体目标旨在检验这一假设：在具体目标 1 中，我们将定义中性粒细胞和上皮细胞对炎症部位 Ado 生成的贡献。具体目标 2 将扩展初步数据以阐明 Ado 介导的 Cullin-2 去 neddylation 的机制。具体目标 3 将探讨 Ado 对 HIF 介导的保护的作用。该提案的总体目标是确定炎症缺氧期间粘膜内 HIF 和 Ado 的新代谢信号。