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.

摘要： 这项提案的主要目的是了解中性粒细胞如何在肠道内迁移。 上皮细胞，最终目标是在病理条件下操纵这一过程，在这种条件下，它 可以变得过度，如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是相关的。 随着中性粒细胞跨结肠上皮迁移的程度和最近的研究 研究表明，中性粒细胞的迁移可以刺激其他介导炎症的细胞的迁移。 因此，中性粒细胞跨上皮细胞在粘膜表面的迁移和聚集是 许多炎症状态，这一过程与临床疾病活动性直接相关。 和上皮损伤。目前，定义中性粒细胞-上皮细胞相互作用的机制 在炎症反应过程中的作用还不完全清楚。为了填补这一知识空白，我们 独一无二地表明二十烷类肝素A3(HxA3)通过顶端分泌 被称为MRP-2的表达外排泵建立了跨细胞的趋化梯度 肠上皮，中性粒细胞从粘膜下间隙进入肠上皮 发炎时的结肠腔。此外，我们还鉴定了N-酰基乙醇胺(NAE) 一类ECB在抑制中性粒细胞跨上皮细胞迁移方面发挥作用，这些 分子通过心尖排出泵分泌，称为P-糖蛋白(P-gp)。我们 假设这些促炎和抗炎通路相互联系，提供一种 反应灵敏的综合机制来控制炎症状态，这些都是不受调控的 在疾病背景下。为了验证这一中心假设，我们的目标是确定HxA3受体(S)在 中性粒细胞表面(目标1)，确定NAE型ECBS/P-gp和HxA3/MRP2的性质 信令(目标2)，并探索这两条路径之间的串扰点，这两条路径驱动 中性粒细胞的炎症功能(目标3)。成功完成这些目标将提供一个 控制中性粒细胞跨肠道迁移的机制的综合图解 这将导致新的生物学原理和治疗干预策略。