生理力学微环境对肝血窦免疫应答的调控机制

Immune responses in liver sinusoid play crucial roles for pathological defenses in human body. Those complicated three-dimensional architecture and corresponding mechanical microenvironment in sinusoids provide physical bases for accomplishing hepatic immune responses. Inherent regulating mechanisms in innate immunity are governed by neutrophil migration dynamics and related intracellular signal transduction mediated by cellular adhesion molecule-ligand interactions from distinct hepatic cells. The scientific issue of this project focuses on elucidating the mechanisms of sinusoidal immune responses under its unique mechanical microenvironment. In combination of experimental measurements with theoretical simulations at the multiscale levels from micro-tissue, cellular, molecular to in vivo animal model, four specific aims are included to investigate: 1) Flow field analysis in hepatic lobule; 2) Neutrophil migration dynamics in liver sinusoid; 3) Intracellular mechanotransductive pathways; and 4) In vivo functional validation upon animal model. The goal of this project is to quantify the impacts of blood flow, micro-structure and cellular components on sinusoidal immune responses and corresponding molecular mechanisms. Such the investigation would deep the understanding in mechanical-biological coupling in liver sinusoid innate immunity, elucidate the relationship between liver sinusoid immunity and hepatic diseases, and enlighten new concepts in immunological therapy of liver diseases.

肝血窦免疫应答是生命体免疫反应的重要组成部分。肝血窦复杂的三维结构与生理力学微环境是实现其免疫应答的物理基础，特定力学微环境下由细胞粘附分子-配体相互作用介导的中性粒细胞迁移动力学以及胞内信号网络的响应动力学是实现其固有免疫应答的内在机制。本项目以生理力学微环境对肝血窦免疫应答调控的内在机制为科学问题，通过实验和模拟相结合，分别从微组织、细胞、分子、动物在体等层次开展以下四个方面的研究：1）肝小叶流场分析；2）肝血窦内中性粒细胞迁移动力学；3）胞内力学信号转导途径；4）动物在体功能验证。预期目标是定量考察肝血窦血流动力学、空间结构以及细胞组成等生理力学微环境对肝血窦免疫应答的调控作用及内在分子机制。本项目的实施将为深入理解肝血窦固有免疫应答的力学-生物学耦合规律，揭示肝血窦免疫特性与肝脏疾病的内在关联，寻找肝脏区域免疫的新治疗方案提供基础。

肝血窦免疫应答是生命体免疫反应的重要组成部分。肝血窦复杂的三维结构与生理力学微环境是实现其免疫应答的物理基础，特定力学微环境下由细胞粘附分子-配体相互作用介导的中性粒细胞迁移动力学以及胞内信号网络的响应动力学是实现其固有免疫应答的内在机制。本项目以生理力学微环境对肝血窦免疫应答调控的内在机制为科学问题，通过实验和模拟相结合，分别从微组织、细胞、分子、动物在体等层次开展了以下四方面的研究：1）肝小叶、肝血窦层次的流场动力学模拟分析，以及力学调控规律；2）离体三维肝血窦模型建立及相应中性粒细胞迁移动力学；3）整合素-配体相互作用介导中性粒细胞迁移动力学的胞内力学信号转导途径；4）在体肝血窦微环境内中性粒细胞迁移动力学。项目通过定量考察肝血窦血流动力学、空间结构以及细胞组成等生理力学微环境对肝血窦免疫应答的调控作用及内在分子机制，为深入理解肝血窦固有免疫应答的力学-生物学耦合规律，揭示肝血窦免疫特性与肝脏疾病的内在关联，寻找肝脏区域免疫的新治疗方案提供基础。