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.

抽象的 促进炎症分辨率和分辨率依赖性肠上皮伤口愈合是最近的 IBD的治疗概念。在炎症解决过程中，巨噬细胞吞噬凋亡中性粒细胞 （胞毒性），从而预防继发性坏死。巨噬细胞吞噬作用也刺激了分泌 各种分辨和修复因素可以引发肠上皮伤口愈合。我以前 报道了巨噬细胞肿瘤的失调和依赖肠道肠上皮伤口的失调 在克罗恩病的鼠模型（CD）中，愈合有助于发病机理。该项目的总体目标 是基于我先前的工作，以推进人类对CD的基于解决方案的疗法的临床前研究。 首先，我试图利用创新的人类模型和公正的分析技术来确定细胞细胞 胚细胞巨噬细胞和人类小肠上皮之间的交流，驱动上皮 炎症损伤后伤口愈合。这项工作将填补重要的知识空白，确定潜力 解决方案特定的治疗靶标，并定义一个物理基线，以评估疾病 - 该分辨率/维修模块的依赖性失调。为了实现第一个目标，我最近已经建模 人类回肠和空肠肠上皮细胞器官培养系统中的炎症性损伤，表明 人类巨噬细胞肿瘤病挽救了这种损伤。我将使用多词技术询问该模型 为了重建潜在的配体 - 受体相互作用和受体信号途径。第二，我试图 调查并翻译靶向巨噬细胞吞噬作用的潜在疾病依赖性失调 和依赖性的人类小肠上皮伤口愈合。我观察到，与 先前的报道，粘膜氧化了多不饱和脂肪酸，包括12-和15-羟基乙烯酸酯 IBD和IBD患者活检中的鼠模型中的酸（Hete）与疾病相关。在我的人类模型中， 这些Hetes充当分辨率的潜在失调剂 依赖性细胞增生的小肠上皮伤口愈合。我将研究这些机制 失调。尽管如此，我以前曾观察到载脂蛋白A1模拟肽4F营救 通过增强疾病高的Hetes的粘膜排泄，鼠类CD样疾病。飞行员数据显示4F 抑制依赖Hete的人类巨噬细胞失调，并增强Hetes在 人小肠原发性上皮。因此，4F似乎是针对Hete依赖性的承诺疗法 分辨率和解决方案修复的失调。在这项研究之后，我预计我会表征小说 炎症分辨率和分辨率依赖性肠上皮修复的失调可能会放大 IBD中的疾病，但是通过利用新型粘膜清除率可以热中破坏这种疾病 路径。