Mechanisms of Adenosine Protection

摘要： 粘液炎性反应涉及中性粒细胞（PMN）的早期积累。没有 在浸润部位有效的PMN清除，PMN可以积聚并导致慢性炎症。 炎性病症，包括溃疡性结肠炎（UC）和克罗恩病（CD）。内 对于这些疾病，定义炎性细胞因子的组分是非常有意义的。 微环境作为了解进展的分子机制的窗口， 分辨率 我们正在进行的这项更新申请的研究表明，中性粒细胞跨上皮 迁移（TEM）导致显著的细胞外酸中毒，部分是通过产生大的 乳酸的量。此外，我们证明了PMN衍生的腺苷（Ado） 显着促进粘膜微环境内的pH稳态。基于这些 新的研究中，我们假设中性粒细胞来源的Ado信号介导的适应性组织 通过促进pH稳态对炎性酸度的反应。 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 肠上皮细胞的乳酸释放和信号轴。在具体目标2中，我们将扩展 初步数据，以确定在治疗期间，细菌介导的pH稳态机制 PMN TEM。具体目标3将利用鼠模型来探测pH稳态在以下中的作用： Ado在体内提供的保护。本提案的总体目标是确定新的 炎症性酸中毒时粘膜内Ado介导的代谢信号传导。

ABSTRACT: Mucosal inflammatory responses involve the early accumulation of neutrophils (PMN). Without efficient PMN clearance at sites of infiltration, PMN can accumulate and contribute to chronic inflammatory conditions, including ulcerative colitis (UC) and Crohn's disease (CD). Within these diseases, there is significant interest in defining components of the inflammatory microenvironment as a window to understanding molecular mechanisms of progression or resolution. Our ongoing studies for this renewal application have revealed that PMN transepithelial migration (TEM) results in significant extracellular acidosis, in part through generation of large amounts of lactate. Moreover, we demonstrate that PMN-derived adenosine (Ado) significantly promotes pH homeostasis within the mucosal microenvironment. Based on thes new studies, we hypothesize that PMN-derived Ado signaling elicits an adaptive tissue response by promoting pH homeostasis to inflammatory acidity. Three specific aims are directed at testing this hypothesis: In Specific Aim 1, we will elucidate the lactate release and signaling axis in intestinal epithelia. In Specific Aim 2, we will extend preliminary data to determine the mechanism(s) of Ado-mediated pH homeostasis during PMN TEM. Specific Aim 3 will utilize murine models to probe the role of pH homeostasis in protection afforded by Ado in vivo. The overall aim of this proposal is to identify novel metabolic signaling mediated by Ado within the mucosa during inflammatory acidosis.