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： 该提案的主要目的是了解中性粒细胞如何穿过肠道迁移 上皮细胞，以达到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 肠道细菌感染。特别是，结肠炎的发生和严重程度似乎相关 与中性粒细胞跨结肠上皮迁移的程度有关，最近的研究表明 研究表明，中性粒细胞迁移可以刺激介导炎症的其他细胞的迁移。 因此，中性粒细胞跨上皮迁移和在粘膜表面的积累是 许多炎症状况，这个过程与临床疾病活动直接相关 和上皮损伤。目前，定义中性粒细胞-上皮相互作用的机制 炎症反应期间的机制尚不完全清楚。为了填补这一知识空白，我们 独特地表明，类二十烷酸 hepoxilin A3 (HxA3) 通过顶端分泌 被称为 MRP-2 的表达外排泵在整个细胞内建立趋化梯度 肠上皮是中性粒细胞从粘膜下间隙移动到 炎症时的结肠腔。此外，我们还发现了 N-酰基乙醇胺 (NAE) 一类 eCB 具有抑制中性粒细胞跨上皮迁移的功能，并且这些 分子通过称为 P-糖蛋白 (P-gp) 的顶端流出泵分泌。我们 假设这些促炎和抗炎途径相互沟通以提供 控制炎症状态的反应性、综合机制，并且这些机制失调 在疾病环境中。为了检验这一中心假设，我们的目标是识别 HxA3 受体 中性粒细胞的细胞表面（目标 1），确定 NAE 型 ECBs/P-gp 和 HxA3/MRP2 的性质 信号传导（目标 2），并探索这两条途径之间的串扰点，从而驱动 中性粒细胞的炎症功能（目标 3）。成功完成这些目标将提供 控制中性粒细胞跨肠道迁移机制的综合图 上皮细胞将导致新的生物学原理和治疗干预策略。