Investigation of Immune Cell Trafficking in Complex Cellular Environment

免疫细胞在组织中的运输对免疫反应是至关重要的，并且可以受到各种环境引导信号的指导，如化学浓度梯度和电场。虽然化学梯度引导的细胞迁移(即趋化)是一个被广泛研究的生物学过程，但免疫细胞如何响应代表体内现实情况的复杂的化学吸引场并不是很清楚。此外，电场引导免疫细胞迁移(即趋电性)的机制还没有明确的定义。由于化学和电场可以在体内共存，并以组合的方式引导免疫细胞迁移，因此出现了额外的复杂性。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，以实现对复杂细胞环境中免疫细胞运输的定量和系统了解。在过去的五年里，我的实验室在确定共存的化学吸引物领域中细胞迁移的指导机制方面取得了重要进展。此外，我们在表征免疫细胞的趋电性及其与趋化性的相互作用方面也取得了进展。在此基础上，在未来五年内，我们将进一步研究免疫细胞在复杂的电化学引导环境中迁移和运输的引导机制。在一个方向上，我们将进一步探索免疫细胞在复杂趋化剂领域中迁移的组合引导机制，重点是趋化物质梯度状态和分布的影响以及趋化物质受体脱敏的作用。我们将使用微流控装置测试原代免疫细胞和表达突变的趋化受体的细胞在不同的趋化梯度配置中的迁移。此外，我们还将进一步开发量化模型，以补充实验研究。在另一个方向上，我们将重点研究化学和电子引导信号在指导免疫细胞迁移方面的竞争。我们将使用微流体装置，它可以产生高度受控的重叠化学梯度和电场，用于细胞迁移分析。此外，我们将使用实验和建模相结合的方法探索几种可能的潜在信号机制，包括受体电迁移和钙信号传递。我预计我的发现计划将对免疫细胞在组织中运输的生物学做出重大贡献，这将与一系列生理问题和疾病高度相关，如伤口愈合、自身免疫性疾病和癌症。此外，我的发现计划将为一系列HQP创造高质量的跨学科培训机会。

Immune cell trafficking in tissues is crucial for immune responses and can be directed by various environmental guiding cues such as chemical concentration gradients and electric fields. Although chemical gradient guided cell migration (i.e. chemotaxis) is a well studied biological process, it is not well understood how immune cells migrate in response to complex chemoattractant fields, which represent the realistic situation in vivo. Furthermore, the mechanisms for electric field directed immune cell migration (i.e. electrotaxis) is not clearly defined. Additional complexity arises since chemical and electric fields can co-exist in vivo and guide immune cell migration in a combinatorial manner. My Discovery research program aims at integrating cell biology and immunology research approaches, biophysical analysis and novel microfluidic tools to achieve a quantitative and systematic understanding of immune cell trafficking in complex cellular environments. Over the past five years, my lab has achieved important progress in identifying guiding mechanisms for cell migration in co-existing chemoattractant fields. In addition, we have progressed in characterizing immune cell electrotaxis and its interactions with chemotaxis. Based on this progress, in the next five years, we will further investigate the guiding mechanisms for immune cell migration and trafficking in complex electrochemical guiding environments. In one direction, we will further explore the combinatorial guiding mechanism for immune cell migration in complex chemoattractant fields with focuses on the effects of chemoattractant gradient states and profiles as well as the role of chemoattractant receptor desensitization. We will test the migration of primary immune cells and cell transfectants expressing mutated chemoattractant receptors in different chemoattractant gradient configurations using microfluidic devices. In addition, we will further develop quantitative models to complement experimental studies. In another direction, we will focus on investigating the competition between chemical and electrical guiding signals in directing immune cell migration. We will employ microfluidic devices that can produce highly-controlled overlapping chemical gradients and electric fields for cell migration analysis. Furthermore, we will explore several possible underlying signalling mechanisms including receptor electromigration and calcium signalling using a combined experimental and modelling approach. I expect my Discovery program to contribute significantly to the biology of immune cell trafficking in tissues, which will be highly relevant to a wide range of physiological problems and diseases such as wound healing, autoimmune diseases and cancers. In addition, my Discovery program will create high quality interdisciplinary training opportunities for a range of HQP.