Neuro-immune regulation of intestinal inflammation

肠道炎症的神经免疫调节

• 批准号: 10462650
• 负责人: David Artis
• 金额: $ 63.7万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462650
• 关键词: Adoptive Cell Transfers; Affect; Allergic; Allergic inflammation; American; Amphiregulin; Attenuated; Biological Products; Biology; Biopsy; Bone Marrow Suppression; Cell Communication; Cell Lineage; Cell physiology; Cells; Chemical Models; Chemicals; Chronic; Chronic Disease; Clinical; Colon; Crohn' s disease; Cytometry; Data; Development; Diarrhea; Disease; Economic Burden; Enteral; Environmental Risk Factor; Epidermal Growth Factor Receptor; Family; Flow Cytometry; Genetic; Genetic Transcription; Healthcare Systems; Helminths; Hemorrhage; Homeostasis; Human; Image; Immune; Immunity; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Integration Host Factors; Intestinal parasite; Intestines; Kinetics; Ligands; Lymphoid Cell; Malignant Neoplasms; Measures; Mediating; Microscopy; Molecular; Mucous Membrane; Mus; Muscle Cramp; Nervous system structure; Neuroimmune; Neuromedin U; Neurons; Neuropeptides; Opportunistic Infections; Pain; Pancreatitis; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Physiological; Population; Production; Proliferating; Property; Public Health; Pulmonary Inflammation; Quality of life; Regulation; Reporter; Risk; Role; Signal Pathway; Signal Transduction; Sodium Dextran Sulfate; Source; Spatial Distribution; Stimulus; Surface; TSLP gene; Testing; Therapeutic; Tissues; Treatment Cost; Ulcerative Colitis; United States; Up-Regulation; associated symptom; attenuation; base; cost; cytokine; gastrointestinal; gut inflammation; health economics; improved; in vivo; injury and repair; insight; intestinal injury; liver inflammation; microbial; microbiota; mouse model; neuromedin U receptor; new therapeutic target; novel; novel therapeutics; pre-clinical; repaired; response; tissue repair

PROJECT SUMMARY Inflammatory bowel diseases, which include both ulcerative colitis and Crohn's disease, are estimated to affect 3 million Americans, and the number of people living with IBD continues to rise. Currently available medications are costly, ineffective for some patients, and associated with serious risks including opportunistic infections, bone marrow suppression, hepatic inflammation, pancreatitis, and cancer. Thus, there is an urgent need to improve our understanding of modulators of intestinal inflammation and repair in order to identify novel therapeutic targets for the treatment of IBD. Innate lymphoid cells (ILCs) are a relatively-recently characterized family of immune cells that are enriched at barrier surfaces and modulate inflammation in response to cytokine and microbial signals. In particular, group 2 ILCs (ILC2s) sense alarmins and cytokines such as IL-25, IL-33, and TSLP, can be activated by the nervous system, and produce type 2 cytokines that promote anti-helminth immunity and allergic inflammation. Furthermore, our lab has shown that ILC2s also exert tissue-protective functions via secretion of the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG), resulting in amelioration of tissue damage following intestinal injury. In new preliminary studies presented here, we show that expression of the neuropeptide, neuromedin U (NMU), is increased during intestinal inflammation in mice, and lack of endogenous NMU results in more severe disease in a model of chemical-induced intestinal damage and inflammation. Conversely, therapeutic administration of NMU results in upregulation of ILC2- derived AREG and ameliorates chemical-induced intestinal damage. Furthermore, similar to in inflamed murine intestines, NMU expression is also elevated in IBD patient biopsies, and the receptor for NMU is detected on human colonic ILCs. Based on our new preliminary data, we hypothesize that enteric neuron-derived NMU activates the tissue-protective functions of ILC2s. We propose to generate a detailed understanding of how NMU mediates tissue protection in both murine models of intestinal inflammation and human IBD. In Aim 1, we will test the hypothesis that during intestinal injury and repair, expression, cellular sources, and spatial pattern of NMU expression are altered. We will also test the role of endogenous enteric-derived NMU in maintaining tissue homeostasis. In Aim 2, we will employ novel reporter mice to directly test the cellular and molecular mechanism by which NMU mediates tissue protection. In Aim 3, we will define the NMU-NMUR1 axis in the healthy human intestine and determine how alterations in NMU-NMUR1 signaling correlate with clinical and endoscopic measures of IBD disease activity. In addition to uncovering fundamental and novel neuropeptide biology and their unique roles in IBD, these studies will provide preclinical justification for development of novel therapeutics to target this pathway.

项目摘要 据估计，包括溃疡性结肠炎和克罗恩病在内的炎症性肠道疾病会影响 300万美国人，与IBD的人数继续增加。目前可用 药物对某些患者的代价高昂，无效，并且与包括机会主义的严重风险有关 感染，骨髓抑制，肝炎，胰腺炎和癌症。因此，有一个紧急的 需要提高我们对肠道炎症和修复调节因子的理解，以识别新颖 治疗IBD的治疗靶标。先天淋巴样细胞（ILC）是一个相对纯粹的表征 在障碍表面富集并根据细胞因子调节炎症的免疫细胞家族 和微生物信号。特别是，第2组ILC（ILC2）感知警报蛋白和细胞因子，例如IL-25，IL-33， TSLP可以被神经系统激活，并产生2型细胞因子，以促进抗螺旋。 免疫力和过敏性炎症。此外，我们的实验室表明ILC2也具有组织保护 通过分泌表皮生长因子受体（EGFR）配体的功能 肠道损伤后的组织损伤改善。在这里介绍的新初步研究中，我们表明 在小鼠肠道炎症过程中，神经肽，神经蛋白U（NMU）的表达增加， 在化学诱导的肠模型中，缺乏内源性NMU导致更严重的疾病 损害和炎症。相反，NMU的治疗施用导致ILC2-上调 衍生的AREG并改善化学诱导的肠损伤。此外，类似于发炎的鼠 IBD患者活检中的肠道，NMU表达也升高，并且在NMU的受体上被检测到 人类结肠ILC。根据我们的新初步数据，我们假设肠神经元衍生的NMU 激活ILC2的组织保护功能。我们建议对如何详细了解 NMU介导了肠炎和人IBD的鼠模型中的组织保护。在AIM 1中，我们 将检验以下假设，即在肠道损伤和修复期间，表达，细胞来源和空间模式 NMU表达的改变。我们还将测试内源性肠源性NMU在维护中的作用 组织稳态。在AIM 2中，我们将采用新型记者小鼠直接测试细胞和分子 NMU介导组织保护的机制。在AIM 3中，我们将定义NMU-NMUR1轴 健康的人类肠子，并确定NMU-NMUR1信号传导的变化与临床和 IBD疾病活动的内窥镜测量。除了发现基本和新颖的神经肽 生物学及其在IBD中的独特角色，这些研究将为发展新颖的临床前辩护 靶向这一途径的治疗剂。