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，治疗选择有限。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信号通路在肠道肿瘤发生中起到了作用。这个项目的主要目标是阐明IL-36R信号在癌症发展中的作用。指定的项目将包括已建立的模型系统的体内研究和肠道肿瘤发生的分子分析，其中将包括对IL-36R缺陷小鼠的研究。IL-36R配体的全身性过表达对肠道肿瘤发生的影响将通过一个基于微环载体的表达系统来研究。微型内窥镜检查将允许对体内肿瘤发展的系列分析。本项目旨在解决以下问题：1.抑制或激活IL-36R对体内肠道稳态有何影响？2.IL-36R信号通路及其在不同结直肠癌模型肿瘤发生、生长和进展过程中的调控作用？3.激活或抑制IL-36R在肿瘤成纤维细胞中诱导肠道肿瘤发生的分子机制？4.是什么触发了结直肠癌中不同IL-36R配体的诱导？5.IL-36R及其配体在人结直肠癌不同阶段的表达模式？综上所述，本项目旨在阐明IL-36R信号在癌的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，该项目可能为开发针对一种常见肿瘤疾病的新的治疗方案提供基础。

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.