Mechanisms of Adenosine Protection

腺苷保护机制

• 批准号: 10322159
• 负责人: Sean P Colgan
• 金额: $ 34.99万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322159
• 关键词: Acidity; Acidosis; Acids; Acute; Adenosine; American; Animal Model; Anti-Inflammatory Agents; Antigens; Bicarbonates; Buffers; Cells; Chronic; Colitis; Crohn' s disease; Cullin 2 Protein; Data; Digestive System Disorders; Disease; Disease Progression; Enzymes; Epithelial; Escherichia coli; Funding; G-Protein-Coupled Receptors; Generations; Goals; Homeostasis; Human; Hypoxia; Hypoxia Inducible Factor; Ileitis; Immune response; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune Response; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Mucositis; Mucous Membrane; Mus; Natural Immunity; Nucleotides; Patients; Permeability; Phase; Physiological; Publishing; Receptor Signaling; Recruitment Activity; Regulation; Resolution; Role; SLC26A3 gene; Signal Transduction; Site; Source; Surface; System; Testing; Tissues; Transcript; Transgenic Mice; Ulcerative Colitis; Work; base; design; diadenosine triphosphate; enhancing factor; experimental study; extracellular; gut inflammation; healing; in vivo; in vivo Model; innovation; insight; interest; intestinal epithelium; knock-down; migration; mouse model; neutrophil; new therapeutic target; novel; nucleotide analog; olfactory receptor; overexpression; pH Homeostasis; response; therapeutic target

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.

摘要： 粘膜炎症反应包括中性粒细胞(PMN)的早期聚集。如果没有 有效清除PMN在渗入部位，PMN可积累并导致慢性 炎症状态，包括溃疡性结肠炎(UC)和克罗恩病(CD)。在 在这些疾病中，有很大的兴趣来定义炎症的成分 微环境是了解疾病进展或发展的分子机制的窗口 决议。 我们正在进行的这一更新应用的研究表明，PMN跨上皮 迁移(TEM)导致严重的细胞外酸中毒，部分是通过生成大量 乳酸量。此外，我们还证明了PMN来源的腺苷(ADO) 显著促进粘膜微环境内的pH动态平衡。基于这些 新的研究，我们假设PMN来源的腺苷信号引起适应性组织 通过促进pH动态平衡对炎性酸度的反应。 三个具体目标旨在检验这一假说：在具体目标1中，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，我们将扩大 腺苷介导的pH动态平衡机制的初步研究(S) PMN透射电子显微镜。特异性目标3将利用小鼠模型来探索pH动态平衡在 在体内由腺苷提供的保护。这项建议的总体目标是确定小说 炎症性酸中毒时粘膜内ADO介导的代谢信号。