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

结直肠癌（CRC）是一种常见的恶性疾病，治疗方法有限。IL-36a、IL-36b和IL-36g是IL-36受体（IL-36R）的配体，属于IL-1相关细胞因子家族。包括自己的工作在内的几条证据表明IL-36R信号通路对肠道肿瘤发生的贡献。该项目的主要目标是阐明IL-36R信号在crc发展中的作用。指定的项目将包括建立模型系统的体内研究和肠道肿瘤发生的分子分析，其中将包括il36r缺陷小鼠的研究。il - 36r配体的系统性过表达对肠道肿瘤发生的影响将在基于微环载体的表达系统的帮助下进行研究。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：IL-36R的抑制或激活对体内肠道稳态的影响是什么？2. 在各种CRC模型中，IL-36R信号通路及其调控在肿瘤起始、肿瘤生长和肿瘤进展中的作用是什么？3. 肿瘤成纤维细胞中IL-36R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. 是什么触发了CRC中不同IL-36R配体的诱导？5. IL-36R及其配体在人crc不同阶段的表达模式是什么？总之，本项目旨在阐明IL-36R信号在crc启动和生长中的作用，并将研究阻断IL-36R通路如何作为一种治疗方法。因此，该项目可能为开发一种常见肿瘤疾病的新治疗方案提供基础。

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.