Investigation of the homeostasis regulation in the intestine1) Role of NO-sensitive guanylyl cyclase in the intestinal ecosystem 2) Characterization of PD-1 expression on intestinal innate lymphoid cells group 2 (ILC2)

肠道内稳态调节的研究 1) NO 敏感鸟苷酸环化酶在肠道生态系统中的作用 2) 肠道先天淋巴细胞组 2 (ILC2) 上 PD-1 表达的表征

• 批准号: 421640644
• 负责人: Dr. Katharina Beck
• 金额: --
• 依托单位: Abteilung Mikrobiologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/421640644?language=en
• 关键词: Investigation; homeostasis; regulation; intestine1; Role

Mucosal sites encounter vast antigens including commensal bacteria, food environmental antigens and pathogens. To maintain homeostasis, unique mechanisms evolved to regulate mucosal immune response.The NO/cGMP signaling pathway plays a crucial role in the gastrointestinal (GI) tract as knockout mice (GCKO), deficient for its key enzyme nitric oxide (NO)-sensitive guanylyl cyclase (GC), suffer from a severe GI phenotype. They die a premature death due to ruptures and hemorrhages in colon and caecum, thus, a special fibre-reduced diet is crucial for survival.In the GI tract NO-GC expression has been shown in cells of the muscle layer and in unidentified cells of the lamina propria. Based on the GI phenotype, NO-GC expression in these cells potentially play a notable role in the maintenance of GI homeostasis.For verification, GCKO mice will be kept under germ-free (GF) and specific-pathogen-free (SPF) conditions. Analysis of bacterial composition and immune cell distribution of GCKO and control mice will identify the effect of NO-GC deficiency on the microbiota. Moreover, the mucus layer and the epithelial barrier will be evaluated to assess mucosal barrier integrity and thus identify early stages of inflammation.To bridge the time gap of GCKO establishment, function of PD-1/PD-L1 expression on intestinal innate lymphoid cells group 2 (ILC2) should be analyzed in an independent project. The negative regulator PD-1 and its ligand PD-L1 have been recently shown to be expressed on ILC2 of lung and small intestine. However, neither the expression of either both, receptor and ligand on a similar cell type, nor expression and function of PD-1/PD-L1 on colonic ILC2 has been determined yet. PD-1/PD-L1 expression will be analyzed by FACS and compared between GF and SPF mice, after antibiotics treatment and in disease models for intestinal inflammation and cancer.Finally, both projects will provide a better understanding of GI homeostasis regulation and may contribute to the improvement of therapies of highly prevalent diseases like GI inflammation and cancer.

粘多糖会遇到大量的抗原，包括肠道细菌、食物环境抗原和病原体。为了维持体内平衡，进化出独特的机制来调节粘膜免疫反应。NO/cGMP信号通路在胃肠道（GI）中发挥着至关重要的作用，因为基因敲除小鼠（GCKO）缺乏其关键酶一氧化氮（NO）敏感的鸟苷酸环化酶（GC），患有严重的GI表型。由于结肠和盲肠的破裂和破裂，它们会过早死亡，因此，特殊的纤维减少饮食对生存至关重要。在胃肠道中，肌肉层细胞和固有层的未识别细胞中显示了NO-GC表达。基于胃肠道表型，这些细胞中的NO-GC表达可能在维持胃肠道稳态中发挥重要作用。对GCKO和对照小鼠的细菌组成和免疫细胞分布的分析将确定NO-GC缺乏对微生物群的影响。此外，粘液层和上皮屏障将被评估，以评估粘膜屏障的完整性，从而确定炎症的早期阶段。为了弥合GCKO建立的时间差距，PD-1/PD-L1表达对肠道先天淋巴细胞2组（ILC 2）的功能应在一个独立的项目中进行分析。近年来研究发现，负调节因子PD-1及其配体PD-L1表达于肺和小肠的ILC 2上。然而，尚未确定受体和配体两者在相似细胞类型上的表达，也未确定PD-1/PD-L1在结肠ILC 2上的表达和功能。PD-1/PD-L1的表达将通过流式细胞仪进行分析，并在GF和SPF小鼠之间、抗生素治疗后以及肠道炎症和癌症的疾病模型中进行比较。最后，这两个项目将更好地了解GI稳态调节，并可能有助于改善高度流行疾病如GI炎症和癌症的治疗。