Dysregulation of inflammation resolution as therapeutic target for IBD

炎症消退失调作为 IBD 的治疗靶点

• 批准号: 10663586
• 负责人: David Meriwether
• 金额: $ 16.31万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663586
• 关键词: Acute; Agonist; Anti-Inflammatory Agents; Apical; Apolipoprotein A-I; Apoptotic; Biopsy; Cell Communication; Cell model; Cells; Chronic; Crohn' s disease; Data; Disease; Eicosanoids; Epithelial Receptor Cell; Epithelium; Excretory function; G-Protein-Coupled Receptors; Goals; Homeostasis; Human; Hydroxyeicosatetraenoic Acids; Immunosuppressive Agents; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Intestinal Mucosa; Knowledge; Ligands; Macrophage; Measures; Methods; Modeling; Mucous Membrane; Mus; Nature; Necrosis; Oral; Organoids; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Polyunsaturated Fatty Acids; Population; Process; Proteomics; RNA Interference; Receptor Signaling; Reporting; Resolution; Role; Signal Pathway; Small Intestines; System; Techniques; Therapeutic; Therapeutic Intervention; Time; Ulcerative Colitis; Work; antagonist; clinical remission; cyclooxygenase 2; epithelial repair; epithelial wound; gut inflammation; healing; human model; innovation; intestinal epithelium; lipid mediator; mouse model; multiple omics; neutrophil; novel; peptidomimetics; pharmacologic; phosphoproteomics; pre-clinical research; prevent; programs; receptor; repaired; response; targeted treatment; therapeutic target; transcriptome sequencing; wound healing

ABSTRACT Promoting inflammation resolution and resolution-dependent intestinal epithelial wound healing are recent therapeutic concepts for IBD. During inflammation resolution, macrophages phagocytose apoptotic neutrophils (efferocytosis), thereby preventing secondary necrosis. Macrophage efferocytosis also stimulates the secretion of various resolving and reparative factors that can trigger intestinal epithelial wound healing. I previously reported that dysregulation of macrophage efferocytosis and efferocytosis-dependent intestinal epithelial wound healing contributed to pathogenesis in a murine model of Crohn’s disease (CD). The overall goal of this project is to build upon my prior work to advance human pre-clinical research into resolution-based therapies for CD. First, I seek to leverage innovative human models and unbiased analytical techniques to determine the cell-cell communication between efferocytic macrophages and human small intestinal epithelium that drives epithelial wound healing following inflammatory injury. This work will fill important knowledge gaps, identify potential resolution-specific therapeutic targets, and define a physiological baseline against which to assess disease- dependent dysregulation of this resolution/repair module. Towards this first goal, I have recently modeled inflammatory injury in human ileal and jejunal intestinal epithelial organoid culture systems and shown that human macrophage efferocytosis rescues this injury. I will interrogate this model with multi-omic techniques in order to reconstruct potential ligand-receptor interactions and receptor-signaling pathways. Second, I seek to investigate and translationally target potential disease-dependent dysregulations of macrophage efferocytosis and efferocytosis-dependent human small intestinal epithelial wound healing. I have observed, consistent with prior reports, that mucosal oxidized polyunsaturated fatty acids including 12- and 15- hydroxyeicosatetraenoic acid (HETE) correlate with disease in murine models of IBD and in IBD patient biopsies. In my human models, these HETEs act as potential dysregulators of resolution—suppressing both macrophage efferocytosis and efferocytosis-dependent small intestinal epithelial wound healing. I will investigate the mechanisms of these dysregulations. Nonetheless, I had previously observed that the apolipoprotein A1 mimetic peptide 4F rescues murine CD-like disease by enhancing mucosal excretion of disease-elevated HETEs. Pilot data show that 4F inhibits HETE-dependent human macrophage dysregulation and enhances the clearance of HETEs across human small intestinal primary epithelium. 4F thus appears to be a promising therapy against HETE-dependent dysregulation of resolution and resolution-repair. After this study, I anticipate that I will have characterized novel dysregulations of inflammation resolution and resolution-dependent intestinal epithelial repair that may amplify disease in IBD but that can nonetheless be disrupted therapeutically by exploiting a novel mucosal clearance pathway.

摘要 促进炎症消退和消退依赖性肠上皮伤口愈合是最近的 IBD的治疗概念。在炎症消退期间，巨噬细胞吞噬凋亡的中性粒细胞 （红细胞增多症），从而防止继发性坏死。巨噬细胞增多症也刺激分泌 各种解决和修复因素，可以触发肠上皮伤口愈合。我以前 报道了巨噬细胞吞噬功能失调和吞噬依赖性肠上皮损伤， 在克罗恩病（CD）的鼠模型中，愈合有助于发病机制。本项目的总体目标 是在我之前的工作基础上，推进人类临床前研究，以解决CD的治疗问题。 首先，我试图利用创新的人类模型和无偏见的分析技术来确定细胞-细胞 巨噬细胞和人小肠上皮之间的通讯， 炎症损伤后的伤口愈合。这项工作将填补重要的知识空白， 分辨率特定的治疗目标，并定义评估疾病的生理基线- 这种解决/修复模块的依赖性失调。为了实现第一个目标，我最近 人回肠和空肠肠上皮类器官培养系统中的炎性损伤， 人巨噬细胞巨噬细胞增多症挽救了这种损伤。我将用多组学技术来研究这个模型， 以重建潜在的配体-受体相互作用和受体信号通路。第二，我寻求 研究和预防性靶向潜在疾病依赖性巨噬细胞吞噬功能失调 和细胞增殖依赖性人小肠上皮伤口愈合。我观察到， 先前的报道，粘膜氧化的多不饱和脂肪酸，包括12-和15-羟基二十碳四烯酸， 在IBD的鼠模型和IBD患者活组织检查中，HETE与疾病相关。在我的人体模型中， 这些HETE作为潜在的溶解调节异常抑制巨噬细胞吞噬细胞和 细胞增殖依赖性小肠上皮创伤愈合。我将研究这些机制 失调尽管如此，我以前观察到载脂蛋白A1模拟肽4F可以挽救 通过增强疾病升高的HETE的粘膜排泄来治疗小鼠CD样疾病。试点数据显示，4F 抑制HETE依赖性人巨噬细胞失调，并增强HETE的清除， 人小肠原代上皮因此，4F似乎是一种有前途的治疗HETE依赖性 分辨率和分辨率修复的失调。经过这次研究，我期望我将有特点的小说， 炎症消退和消退依赖性肠上皮修复失调， 但是仍然可以通过利用新的粘膜清除来治疗性地破坏IBD中的疾病 通路