Neuro-immune regulation of intestinal inflammation

项目总结 炎症性肠病，包括溃疡性结肠炎和克罗恩病，据估计会影响 300万美国人，而且IBD患者的数量还在继续上升。目前可用 药物治疗昂贵，对一些患者无效，并与包括机会主义在内的严重风险相关 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因子的理解，以便识别新的 IBD治疗的治疗靶点。先天淋巴样细胞(ILCs)是一种相对较新的 一种免疫细胞家族，在屏障表面富含，并对细胞因子做出反应来调节炎症 和微生物信号。特别地，第2组ILC(ILC2)感应警报和细胞因子，如IL-25、IL-33 和TSLP，可以被神经系统激活，并产生促进抗蠕虫的2型细胞因子 免疫力和过敏性炎症。此外，我们的实验室还表明，ILC2还具有组织保护作用 通过分泌表皮生长因子受体(EGFR)配体双调节蛋白(AREG)发挥功能，导致 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 神经肽神经肽U(NMU)的表达在小鼠肠道炎症过程中增加， 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的治疗性应用会导致ILC2- 衍生的AREG和改善化学诱导的肠道损伤。此外，类似于发炎的小鼠 肠组织中，NMU在IBD患者活检组织中的表达也升高，NMU的受体在 人结肠ILCs。根据我们新的初步数据，我们假设肠道神经元来源的NMU 激活ILC2s的组织保护功能。我们建议详细了解如何 NMU在小鼠肠炎模型和人类IBD模型中都具有组织保护作用。在目标1中，我们 将检验假设，在肠道损伤和修复期间，表达、细胞来源和空间模式 NMU的表达发生了改变。我们还将测试内源性肠源性NMU在维持 组织动态平衡。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，我们将定义NMU-NMUR1轴 并确定NMU-NMUR1信号的改变如何与临床和 IBD疾病活动性的内窥镜测量。除了发现基础和新的神经肽 生物学及其在IBD中的独特作用，这些研究将为新药的开发提供临床前证据 以此为靶点的治疗技术。

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.