Neuro-immune regulation of intestinal inflammation

肠道炎症的神经免疫调节

基本信息

批准号：
10097714
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
项目类别：
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/10097714
关键词：
Adoptive Cell Transfers Affect Allergic Allergic inflammation American Amphiregulin Attenuated Biological Biology Biopsy Bone Marrow Suppression Cell Communication Cell Lineage Cell physiology Cells Chemical Models Chemicals Chronic Chronic Disease Clinical Colon Crohn&apos 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 Hepatic Homeostasis Human Image Immune Immunity Individual Inflammation Inflammatory Inflammatory Bowel Diseases Injury Integration Host Factors Intestinal parasite Intestines Kinetics Ligands Lung 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 Pharmaceutical Preparations Physiological Population Production Proliferating Property Public Health 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 health economics improved in vivo inflammatory disease of the intestine injury and repair insight intestinal injury microbial microbiota mouse model neuromedin U receptor new therapeutic target novel novel therapeutics pre-clinical repaired response tissue repair

项目摘要

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.

项目概要炎症性肠病，包括溃疡性结肠炎和克罗恩病，估计会影响 300 万美国人，患有 IBD 的人数持续增加。目前可用药物治疗费用昂贵，对某些患者无效，并且存在严重风险，包括机会性风险感染、骨髓抑制、肝脏炎症、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剂的理解，以便识别新的 IBD 治疗的治疗靶点。先天淋巴细胞 (ILC) 是一种相对较新的特征免疫细胞家族，在屏障表面富集并响应细胞因子调节炎症和微生物信号。特别是，第 2 组 ILC (ILC2) 可感知警报素和细胞因子，例如 IL-25、IL-33、和 TSLP，可以被神经系统激活，产生促进抗蠕虫的 2 型细胞因子免疫和过敏性炎症。此外，我们的实验室已表明 ILC2 还发挥组织保护作用通过分泌表皮生长因子受体 (EGFR) 配体双调蛋白 (AREG) 发挥作用，从而产生改善肠道损伤后的组织损伤。在这里提出的新的初步研究中，我们表明小鼠肠道炎症期间神经肽神经调节素 U (NMU) 的表达增加，在化学诱导的肠道模型中，内源性 NMU 的缺乏会导致更严重的疾病损伤和炎症。相反，NMU 的治疗性给药会导致 ILC2- 的上调衍生的 AREG 并改善化学引起的肠道损伤。此外，类似于发炎的小鼠在肠道中，IBD 患者活检中 NMU 表达也升高，并且在肠道中检测到 NMU 受体人类结肠 ILC。根据我们新的初步数据，我们假设肠神经元衍生的 NMU 激活 ILC2 的组织保护功能。我们建议详细了解如何 NMU 在小鼠肠道炎症模型和人类 IBD 模型中介导组织保护。在目标 1 中，我们将检验以下假设：在肠道损伤和修复过程中，表达、细胞来源和空间模式 NMU 表达发生改变。我们还将测试内源性肠源性 NMU 在维持组织稳态。在目标2中，我们将使用新型报告小鼠来直接测试细胞和分子 NMU 介导组织保护的机制。在目标 3 中，我们将在健康人肠道并确定 NMU-NMUR1 信号传导的改变如何与临床和 IBD 疾病活动的内窥镜测量。除了发现基本的和新颖的神经肽生物学及其在 IBD 中的独特作用，这些研究将为新型药物的开发提供临床前依据。针对该途径的治疗。