Investigation of Immune Cell Trafficking in Complex Cellular Environment

背景：免疫细胞的运输对于免疫细胞的生物学来说是至关重要的，与生理过程直接相关。免疫细胞的运输受到各种微环境因素的调控，如化学浓度梯度和电场。电化学场引导的细胞迁移在体外和体内都得到了很好的证实。然而，潜在的机制还远未得到很好的理解。特别是，缺乏关于免疫细胞如何响应复杂的环境引导信号的知识，这些信号是相互耦合的，在空间和时间上动态变化。我之前通过发现基金的研究发现了CCR7介导的T细胞迁移的有趣的组合引导机制，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，这促使了进一步的探索。长期目标：我的发现研究计划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。下一个五年的研究计划：我的发现号研究计划在未来五年将通过以下目标重点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：目的I：研究CCR7介导的T细胞在复杂化学吸引剂领域中迁移的引导机制。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-磷酸共存区域；2)CCR7配体和CXCL13共存区域介导的。目的II：检测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)免疫细胞对动态变化的EF的迁移行为。目的：探讨电化学场中细胞间的迁移相互作用。我将指导我的研究计划的这一部分，以探索细胞-细胞迁移相互作用是如何1)由EF单独调节；以及2)由共存的化学场和EF介导的。意义：这项工作将大大有助于理解免疫细胞迁移和贩运的复杂过程。重要的是，通过我的发现计划进行的跨学科培训将培养能够在物理科学、工程和生命科学之间进行研究的年轻科学家。除了在细胞迁移方面获得坚实的科学背景外，学生还将接受动手研究技能的培训，并发展强大的科学交流能力，从而为他们在学术和工业领域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.