Mechanisms of Adenosine Protection

 描述（由申请方提供）：粘液性炎症伴随组织代谢的显著变化。炎症的主要代谢特征之一是组织缺氧，其最近被认为显著影响炎症性疾病的结果。在疾病过程的早期，这种“炎性缺氧”在很大程度上是由于需要氧的炎性细胞类型，特别是嗜中性粒细胞的募集。在过去的两年中，我们在定义我们最初的假设方面取得了重大进展，即腺苷（Ado）在炎症反应早期产生，通过直接作用于粘膜缺氧诱导因子（HIF）稳定，起到前馈抗炎机制的作用。利用新的体外系统，新的小鼠炎症模型和患者来源的材料，这项工作揭示了一些重要的功能与抗炎Ado信号转导机制。正在进行的工作已经定义了一个关键的信号传导轴，其中核苷酸代谢通过cullin neddylation和HIF稳定所需的E3连接酶与HIF转录网络中心偶联。同样，这项工作已经确定了一个以前不受重视的来源，粘膜核苷酸释放的激活PMN，并提供了一个潜在的丰富来源的Ado在活动性炎症。基于这些初步研究，我们假设急性炎症过程中产生的核苷酸直接影响粘膜HIF的稳定性和功能。三个具体目标是针对测试这一假设：在具体目标1，我们将阐明粘膜中的核苷酸代谢机制。具体目标2将定义粘膜炎症期间胞外酶对Ado生成的相对贡献。具体目标3将检查PMN衍生的核苷酸对上皮HIF提供的粘膜保护的贡献。本研究的总体目标是通过HIF和Ado在炎症性缺氧过程中在粘膜内识别新的代谢信号。

 DESCRIPTION (provided by applicant): Mucosal inflammation is accompanied by substantial shifts in tissue metabolism. One of the major metabolic signatures of inflammation is tissue 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 the past two years, we have made significant progress toward defining our original hypothesis that adenosine (Ado) generated early in the inflammatory response functions as a feed- forward anti-inflammatory mechanism through direct actions on mucosal hypoxia- inducible factor (HIF) stabilization. Utilizing new in vitro systems, novel murine models of inflammation and patient-derived materials, this work has revealed a number of important features related to mechanisms of anti-inflammatory Ado signaling. Ongoing work has defined a critical signaling axis wherein nucleotide metabolism is centrally coupled the HIF transcriptional network via cullin neddylation and the E3 ligase necessary for HIF stabilization. Likewise, this work has identified a previously unappreciated source of mucosal nucleotide released by activated PMN and provides a potentially rich source of Ado during active inflammation. Based on these preliminary studies, we hypothesize that nucleotides generated during acute inflammation directly impacts mucosal HIF stabilization and function. Three specific aims are directed at testing this hypothesis: In Specific Aim 1, we will elucidate mechanisms of nucleotide metabolism in the mucosa. Specific Aim 2 will define the relative contribution of ecto-enzymes to Ado generation during mucosal inflammation. Specific Aim 3 will examine the contribution of PMN-derived nucleotides on mucosal protection afforded by epithelial HIF. The overall aim of this proposal is to identify nove metabolic signaling by HIF and Ado within the mucosa during inflammatory hypoxia.