Investigation of Immune Cell Trafficking in Complex Cellular Environment

背景：免疫细胞运输对免疫细胞生物学至关重要，与生理过程直接相关。免疫细胞的运输是由各种微环境因素如化学浓度梯度和电场（EF）精心策划的。在体内和体外，由电化学场引导的细胞迁移已经得到了很好的证明。然而，潜在的机制还远没有被很好地理解。特别是，缺乏关于免疫细胞如何响应复杂的环境引导信号而迁移的知识，这些信号是相互耦合的，并且在空间和时间上动态变化。我之前通过Discovery基金的研究发现了有趣的ccr7介导的T细胞迁移组合引导机制，免疫细胞在化学场和EF中的迁移记忆效应，以及不同类型细胞在复杂的引导微环境中的迁移相互作用，这些都是我进一步探索的动力。长期目标：我的发现研究项目旨在整合细胞生物学和免疫学研究方法，生物物理分析和新型微流体工具，以更好地了解复杂细胞环境中的免疫细胞运输。未来五年的研究计划：我的“发现”研究计划将在未来5年通过以下目标，批判性地研究复杂电化学引导环境中免疫细胞迁移和细胞-细胞相互作用的基本机制：目标一：研究复杂化学引诱剂领域中ccr7介导的T细胞迁移的指导机制。重点是更好地了解T细胞迁移是如何通过1)CCR7配体和鞘氨醇-1-磷酸共存的领域介导的；2) CCR7配体与CXCL13共存场。目的二：探讨免疫细胞在电化学场中迁移的记忆效应。在这个方向上，我将研究1)时空变化的化学场对免疫细胞迁移的影响；2)免疫细胞迁移行为对动态变化EF的响应。目的三：探讨电化学领域中细胞-细胞迁移相互作用。我将指导我的研究计划的这一部分来探索细胞-细胞迁移相互作用是如何被EF单独介导的；2)化学场与EF共存。意义：本工作将有助于理解免疫细胞迁移和转运的复杂过程。重要的是，通过我的发现项目进行的跨学科培训将培养能够在物理科学、工程和生命科学的界面上进行研究的年轻科学家。除了获得扎实的细胞迁移科学背景外，学生还将接受实践研究技能的培训，培养强大的科学沟通能力，从而为他们在学术和工业部门的职业生涯做好准备。

BACKGROUND: Immune cell trafficking is fundamentally important for the biology of immune cells with direct relevance to physiological processes. The trafficking of immune cells is orchestrated by various microenvironmental factors such as chemical concentration gradients and electric fields (EF). Cell migration directed by electrochemical fields have been well demonstrated in vitro and in vivo. However, the underlying mechanisms are far from being well understood. Particularly, there is a lack of knowledge about how immune cells migrate in response to complex environmental guiding signals that are inter-coupled and dynamically vary in space and time. My previous studies through the Discovery grant identified the interesting CCR7-mediated combinatorial guiding mechanism for T cell migration, the migratory memory effect of immune cells in chemical fields and EF, and migratory interactions between different cell types in complex guiding microenvironment, which motivated further explorations. LONG-TERM GOAL: My Discovery research program aims at integrating cell biology and immunology research approaches, biophysical analysis and novel microfluidic tools to achieve a better understanding of immune cell trafficking in complex cellular environments. NEXT FIVE-YEAR RESEARCH PLANS: My Discovery research program in the next 5 year will critically investigate the fundamental mechanisms for immune cell migration and cell-cell interactions in complex electrochemical guiding environments through the following objectives: Objective I: Investigate CCR7-mediated guiding mechanism for T cell migration in complex chemoattractant fields. The focus is to better understand how T cell migration is mediated by 1) co-existing fields of CCR7 ligands and Sphingosine-1-phosphate; 2) co-existing fields of CCR7 ligands and CXCL13. Objective II: Examine the memory effect of immune cell migration in electrochemical fields. In this direction, I will research 1) the impact of spatiotemporally varying chemical fields on immune cell migration; 2) immune cell migratory behavious in response to dynamically changing EF. Objective III: Explore cell-cell migratory interactions in electrochemical fields. I will direct this part of my research program to explore how cell-cell migratory interactions are mediated 1) by EF alone; and furthermore 2) by co-existing chemical fields and EF. SIGNIFICANCE: This work will contribute significantly to the understanding of the complex process of immune cell migration and trafficking. Importantly, the interdisciplinary training through my Discovery program will develop young scientists able to conduct research at the interfaces of physical sciences, engineering and life sciences. In addition to acquiring a solid scientific backgrounds in cell migration, the students will be trained for hands-on research skills and develop strong scientific communication ability thereby preparing them for careers in both academic and industrial sectors.