Neuro-immune regulation of intestinal inflammation

项目摘要 据估计，炎症性肠病，包括溃疡性结肠炎和克罗恩病， 300万美国人，患有IBD的人数继续上升。当前可用 药物治疗昂贵，对某些患者无效，并伴有严重的风险，包括机会性 感染、骨髓抑制、肝脏炎症、胰腺炎和癌症。因此，迫切需要 需要提高我们对肠道炎症和修复调节剂的理解，以确定新的 治疗IBD的治疗靶点。先天性淋巴样细胞（ILC）是一个相对最近的特点， 在屏障表面富集并响应细胞因子调节炎症的免疫细胞家族 和微生物信号。特别地，第2组ILC（ILC 2）感测警报素和细胞因子，例如IL-25、IL-33、IL-24和IL-25。 和TSLP，可以被神经系统激活，并产生2型细胞因子，促进抗蠕虫 免疫和过敏性炎症。此外，我们的实验室已经表明，ILC 2也发挥组织保护作用， 通过分泌表皮生长因子受体（EGFR）配体双调蛋白（AREG）发挥作用， 改善肠损伤后的组织损伤。在这里介绍的新的初步研究中，我们表明 神经肽神经介肽U（NMU）的表达在小鼠肠道炎症期间增加， 而内源性NMU的缺乏在化学诱导的肠道炎症模型中导致更严重的疾病。 损伤和炎症。相反地，NMU的治疗性施用导致ILC 2 - 3的上调。 衍生的AREG并改善化学诱导的肠损伤。此外，与发炎的小鼠相似， 在IBD患者的活检组织中，NMU的表达也升高，并且NMU的受体在IBD患者的小肠中检测到。 人结肠ILC。基于我们新的初步数据，我们假设肠神经元源性NMU 激活ILC 2的组织保护功能。我们建议详细了解如何 NMU在肠道炎症和人IBD的鼠模型中介导组织保护。目标1： 将检验这一假设，即在肠损伤和修复过程中，表达、细胞来源和空间模式 NMU的表达发生了变化。我们还将测试内源性肠源性NMU在维持细胞增殖中的作用。 组织内稳态在目标2中，我们将使用新型报告小鼠直接检测细胞和分子水平， NMU介导组织保护的机制。在目标3中，我们将定义NMU-NMUR 1轴， 健康人肠道，并确定NMU-NMUR 1信号传导的改变如何与临床和 IBD疾病活动性的内镜测量。除了发现基本的和新的神经肽 这些研究将为开发新的治疗IBD的药物提供临床前依据。 针对这一途径的治疗方法。

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.