Molecular investigations into the role of IL-36 receptor signaling for colorectal tumorigenesis

IL-36 受体信号传导在结直肠肿瘤发生中作用的分子研究

• 批准号: 248764882
• 负责人: Privatdozent Dr. Clemens Neufert, Ph.D.
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/248764882?language=en
• 关键词: Molecular; investigations; into; role; IL

Colorectal cancer (CRC) is a frequent malignant disease with limited therapeutic options. IL-36a, IL-36b und IL-36g are ligands of the IL-36 receptor (IL-36R) and belong to the family of IL-1 related cytokines. Several lines of evidence including own work suggest a contribution of the IL-36R signalling pathway to intestinal tumorigenesis. The main goal of this project is to elucidate the role of IL-36R signalling for the development of CRCs.The designated project will comprise in vivo studies with established model systems and molecular analyses of intestinal tumorigenesis which will include work with IL36R-deficient mice. The consequences of systemic overexpression of IL-36R-ligands on intestinal tumorigenesis will be studied with help of a minicircle-vector based expression system. Mini-endoscopy will allow for serial analyses of tumor development in vivo. The designated project aims to address the following questions: 1. What are the consequences of the inhibition or the activation of the IL-36R on the intestinal homeostasis in vivo? 2. What is the role of the IL-36R signalling pathway and its modulation during tumour initiation, tumour growth and tumour progression in various models of CRC? 3. What molecular mechanisms related to intestinal tumour development are induced by the activation or the inhibition of the IL-36R in tumour fibroblasts? 4. What triggers the induction of the different IL-36R ligands in CRC? 5. What are the expression patterns of the IL-36R and its ligands at different stages of human CRCs? In conclusion, this project aims to clarify the role of the IL-36R signalling for the initiation and the growth of CRCs, and it will be studied how the blockade of the IL-36R pathway could serve as a therapeutic approach. Thus, this project may provide a basis for the development of novel therapeutic options for a frequent tumour disease.

结直肠癌（CRC）是一种常见的恶性疾病，治疗选择有限. IL-36 a、IL-36 b和IL-36 g是IL-36受体（IL-36 R）的配体，并且属于IL-1相关细胞因子家族。包括自身工作在内的几条证据表明IL-36 R信号通路对肠道肿瘤发生有贡献。是项计划的主要目的是研究白细胞介素36受体信号在癌症研究中心发展中的作用，包括利用已建立的模型系统进行体内研究，以及对肠道肿瘤发生进行分子分析，其中包括利用白细胞介素36受体缺陷小鼠进行研究。将借助于基于微环载体的表达系统研究IL-36 R配体的系统性过表达对肠肿瘤发生的后果。微型内窥镜将允许对体内肿瘤发展进行系列分析。 指定项目旨在解决以下问题：1.体内IL-36 R的抑制或激活对肠道内稳态的影响是什么？2.在各种CRC模型中，IL-36 R信号通路及其调节在肿瘤发生、肿瘤生长和肿瘤进展过程中的作用是什么？3.肿瘤成纤维细胞中IL-36 R的激活或抑制诱导了哪些与肠道肿瘤发展相关的分子机制？4.什么触发了CRC中不同IL-36 R配体的诱导？5. IL-36 R及其配体在人CRC不同阶段的表达模式是什么？总之，该项目旨在阐明IL-36 R信号传导在CRCs启动和生长中的作用，并将研究IL-36 R通路的阻断如何作为治疗方法。因此，该项目可能为开发常见肿瘤疾病的新治疗方案提供基础。