MST激酶复合物调控肺免疫稳态及疾病的关键细胞功能与信号机制

The regional immunity and homeostasis of lung is critically involved in lung 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 lung immune homeostasis 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 function and signaling mechanism of the MST superamolecular complex, uncovering a new regulatory mode of the TLR and Hippo signaling pathway, as well as its deregulation in diseases (Nat Immunol,2015;Cancer Cell，2014). Meanwhile, we found that MST can interact with multiple signaling pathways and mediate their crosstalks to regulate inflammation (unpublished data).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 MST complex, but will focus on the aspects relevant to the cellular network, signaling transduction pathways and molecular mechanisms regulating regional immunity of lung. A variety of research methods and systems including immunology, cell signaling, protein structure and animal model will be combined to find novel molecules with critical functions during physiological maintenance of lung immune homeostasis, and to define the in-depth pathological alterations of lung immunity especially the function of multi-cellular regulation during tumorigensis. These proposed studies will provide a platform for the discovery of new drug target and the design of next-generation anti-cancer strategy.

肺区域免疫特性与肺癌等肺部疾病发生发展及肿瘤肺转移密切相关。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，但却并不十分清楚肺区域免疫稳态影响肿瘤发生发展及转移扩散的深层病理机制，肿瘤进程中肺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MST激酶复合物功能及其信号转导机制进行研究，阐释了MST激酶与TLR、Hippo信号通路互作的功能机制及其在感染性疾病和肿瘤等病理条件下的作用(Nat Immunol，2015；Cancer Cell，2014)，并发现MST参与调控RLR等信号转导通路。本项目将从MST激酶复合物入手，揭示维持和调控肺区域免疫稳态的细胞网络、信号通路及分子机制，发现其中关键功能分子，深入剖析肺癌发生发展及肿瘤肺转移过程中肺区域免疫特性的病理变化机制，为发现新的药物靶点和肿瘤诊疗策略提供理论基础。

肺区域免疫特性与肺癌等肺部疾病发生发展及肿瘤肺转移密切相关。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，但却并不十分清楚肺区域免疫稳态影响肿瘤发生发展及转移扩散的深层病理机制，肿瘤进程中肺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。本项目着眼于研究肺区域免疫稳态的维持与调控机制，结合细胞生物学、模式动物、结构生物学、生物化学、临床分析等技术和方法，探究以肿瘤相关巨噬细胞（TAMs）为侧重的调控肺区域免疫特性的关键细胞功能，并重点围绕MST激酶复合物与Hippo信号转导网络的关系，在分子水平上阐释肺区域免疫特性的调控机制及其在肿瘤发生发展与转移扩散过程重点病理变化。我们确认了MST维持肺区域免疫稳态的关键细胞功能及关键信号通路，分析了MST4-SLMAP关键功能分子的生化与结构特征并靶向MST复合物开展了药物筛选，深入解析MST激酶调控Hippo信号转导网络调控肺稳态的具体功能作用和分子机制。