STRIPAK相关信号网络调控肠道区域免疫特性的关键细胞功能及病理机制

The regional immunity and homeostasis of gastrointestinal tract is crtically involved in intestinal tumorigenesis. Although both avoiding immune destruction and tumor promoting inflammation are increasingly recognized as hallmarks of cancer, yet it is remains unclear mechanistically how regional immunity and homeostasis of gastrointestinal tract are deregulated to affect tumor progression; and what is the key machinery connecting regional immunity and cancer. Lack of knowledge regarding these aspects hinders the effort to develop novel immunology theory and anti-cancer strategy. Previously, we have dissected the biochemical and structural features of the STRIPAK (striatin interacting phosphatase and kinase) supramolecular complex and studied its function and mechanisms in gastric and colorectal cancers, uncovering a new regulatory mode of the Hippo signaling pathway, as well as its degreulation in tumor (Cancer Cell, 2014). Meanwhile, we found that STRIPAK can interact with multiple signaling pathways and mediate their crosstalks to regulate inflammation (unpublished data). In this project, we aim to continue working on the STRIPAK complex, but will focus on the aspects relevant to the cellular network, signaling transduction pathways and molecular mechanisms regulating intestinal immunity. A variety of research methods and systems including immunology, cell signaling, protein structure and animal model will be combined to find novelmolecules with critical functions during physiological maintainance of gut homeostasis, and to define the in-depth pathlogical alterations of gut immunity especially the function of macrophages during tumoregensis. These proposed studies will provide a platform for the discovery of new drug target and the design of next-generation anti-cancer strategy.

肠道区域免疫稳态的维持与肠道疾病特别是肿瘤的发生发展密切相关。尽管人们已经逐步认识到慢性炎症和免疫逃逸是肿瘤发生发展的两大重要标识，但却并不十分清楚肠道区域免疫稳态影响肿瘤发生的深层病理机制，肿瘤进程中肠道区域免疫特性如何改变也有待阐明。这些问题均阻碍了免疫学理论与肿瘤诊治策略的整体发展。我们前期工作围绕STRIPAK复合物及其在胃癌和结肠癌中功能机制进行研究，阐释了Hippo信号通路在肿瘤发生发展中的失调机制(Cancer Cell，2014)，并发现STRIPAK与Hippo、Wnt、TGFβ、TLR、RLR等信号转导通路相互作用调控免疫炎症(未发表数据)。本项目将从STRIPAK复合物入手，揭示调控肠道区域免疫特性的细胞网络、信号通路及分子机制，发现其中关键功能分子，深入剖析肠癌发生发展过程中巨噬细胞功能特点，为发现新的药物靶点和肿瘤诊疗策略提供理论基础。

肠道区域免疫稳态的维持与肠道疾病特别是肿瘤的发生发展密切相关。尽管人们已经逐步认识到慢性炎症和免疫逃逸是肿瘤发生发展的两大重要标识，但却并不十分清楚肠道区域免疫稳态影响肿瘤发生的深层病理机制，肿瘤进程中肠道区域免疫特性如何改变也有待阐明。这些问题均阻碍了免疫学理论与肿瘤诊治策略的整体发展。我们前期工作围绕STRIPAK复合物及其在胃癌和结肠癌中功能机制进行研究，阐释了Hippo信号通路在肿瘤发生发展中的失调机制(Cancer Cell，2014)，并发现STRIPAK与Hippo、Wnt、TGFβ、TLR、RLR等信号转导通路相互作用调控免疫炎症。本项目从STRIPAK复合物入手，发现了关键激酶MST4磷酸化beta-catenin，调控Wnt信号通路，参与结肠癌的发生发展。揭示了Hippo-Wnt信号通路cross-talk从而调控肠道区域免疫特性的细胞网络、信号通路及分子机制，发现其中关键功能分子MST4，深入剖析肠癌发生发展过程中巨噬细胞功能特点，为发现新的药物靶点和肿瘤诊疗策略提供理论基础。