Control of Neutrophilic Inflammation in Intestinal Health and Disease

控制肠道健康和疾病中的中性粒细胞炎症

• 批准号: 10671690
• 负责人: Beth A McCormick
• 金额: $ 59.58万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671690
• 关键词: ABCB1 gene; ATP-Binding Cassette Transporters; Acute; Address; Agonist; Anti-Inflammatory Agents; Apical; Bacterial Infections; Biological; Biological Assay; CNR2 gene; Cannabinoids; Cell surface; Cells; Chemotactic Factors; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Colitis; Colon; Communication; Disease; Eicosanoids; Ensure; Enteral; Epithelial Cells; Epithelium; Ethanolamines; Event; Family; Goals; Health; Homeostasis; Host Defense; Human; Immune; Immunotherapeutic agent; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Intervention; Intestinal Mucosa; Intestines; Invaded; Investigational Therapies; Knock-in; Knock-out; Knowledge; Mediating; Microfluidic Microchips; Modeling; Molecular; Mucositis; Mucous Membrane; Nature; Neutrophil Infiltration; Pathologic; Pathway interactions; Pharmacologic Actions; Pilot Projects; Play; Process; Protocols documentation; Receptor Activation; Regulation; Regulatory Pathway; Role; Severities; Signal Transduction; Stimulus; Submucosa; Surface; System; Testing; Therapeutic Intervention; Work; arm; efflux pump; endocannabinoid signaling; epithelial injury; experimental study; first responder; follow-up; genome editing; healing; immunoregulation; in vivo Model; insight; intestinal epithelium; member; microorganism; migration; neutrophil; novel; novel therapeutic intervention; positive allosteric modulator; receptor; receptor binding; receptor function; recruit; response; restraint; sensor; validation studies

Summary: The main objective of this proposal is to understand how neutrophils migrate across the intestinal epithelia, toward the eventual goal of manipulating this process in pathologic conditions where it can become excessive as in the context of idiopathic inflammatory intestinal disease as well as enteric bacterial infection. In particular, occurrence and severity of colitis appears to be correlated with the extent of neutrophil transmigration across the colonic epithelium and recent studies have shown that neutrophil migration can incite the migration of other cells that mediate inflammation. Thus, neutrophil transepithelial migration and accumulation at mucosal surfaces is a hallmark of many inflammatory conditions, and this process correlates directly with clinical disease activity and epithelial injury. Currently, the mechanisms that define neutrophil-epithelial interactions during an inflammatory response are not completely understood. To fill this gap in knowledge, we have uniquely shown that secretion of the eicosanoid hepoxilin A3 (HxA3) through the apically expressed efflux pump known as MRP-2 establishes the chemotactic gradient across the intestinal epithelium that is required for neutrophils from the submucosal space to move into the colonic lumen at times of inflammation. Additionally, we identified the N-acyl ethanolamine (NAE) class of eCBs to function in suppressing neutrophil transepithelial migration, and that these molecules are secreted through the apical efflux pump known as P-glycoprotein (P-gp). We hypothesize that these pro- and anti-inflammatory pathways communicate to provide a responsive, integrated mechanism to control inflammation status and that these are dysregulated in disease settings. To test this central hypothesis, we aim to identify the HxA3 receptor(s) on the cell surface of neutrophils (Aim 1), determine the nature of NAE-type ECBs/P-gp and HxA3/MRP2 signaling (Aim 2), and to explore crosstalk points between these two pathways that drive the inflammatory function of neutrophils (Aim 3). Successful completion of these Aims will provide a consolidated picture of mechanisms controlling neutrophil transmigration across the intestinal epithelium that will lead to both novel biological principles and therapeutic intervention strategies.

概括： 该提议的主要目的是了解中性粒细胞如何遍及肠道 上皮，朝着在病理条件下操纵这一过程的最终目标 在特发性炎症性肠道疾病以及 肠细菌感染。特别是，结肠炎的发生和严重程度似乎是相关的 随着跨结肠上皮和最近研究的中性粒细胞跨移民的程度 表明嗜中性粒细胞迁移可以促进其他介导炎症的细胞的迁移。 因此，嗜中性粒细胞旋转迁移和粘膜表面的积累是 许多炎症状况，此过程与临床疾病活动直接相关 和上皮损伤。当前，定义中性粒细胞上皮相互作用的机制 在炎症过程中，尚不完全了解。为了填补知识的差距，我们 独特地表明，eicosanoid肝素A3（HXA3）通过顶端分泌 称为MRP-2的外排泵建立了跨整个趋化梯度 从粘膜下空间中嗜中性粒细胞所需的肠上皮才能进入 炎症时的结肠腔。此外，我们确定了N-酰基乙醇胺（NAE） ECB类在抑制中性粒细胞transepithialial迁移中起作用，这些 分子通过称为P-糖蛋白（P-gp）的根尖外排泵分泌。我们 假设这些促和抗炎途径可以提供 响应迅速的集成机制控制炎症状态，并且这些机制失调 在疾病环境中。为了检验这一中心假设，我们旨在确定HXA3受体 中性粒细胞的细胞表面（AIM 1），确定NAE型ECB/P-GP和HXA3/MRP2的性质 信号传导（AIM 2），并探索这两种驱动的途径之间的串扰点 中性粒细胞的炎症功能（AIM 3）。这些目标的成功完成将提供 控制肠道中性粒细胞转移的机制的合并图片 上皮将导致新颖的生物学原理和治疗干预策略。