Investigation of immune cell trafficking in complex cellular environment

免疫细胞在组织中的运输是免疫反应的关键，并受各种环境信号的调节，如黏附分子和化学诱导剂。过去的研究重点集中在单个黏附分子和趋化物质在引导免疫细胞运输中的作用，以及细胞检测和响应简化的恒定黏附和迁移信号的生物学机制。由于细胞在体内暴露于多个时空变化的定向信号中，了解免疫细胞在复杂细胞环境中的运输对基础科学和临床研究都具有重要意义。但很少有研究试图研究如此具有挑战性的复杂性。我的发现计划的长期目标旨在整合细胞生物学和免疫学方法、生物物理分析和新的微流体工具，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。在第一个授权期，我的重点是了解免疫细胞在复杂的化学吸引剂场中的迁移。我将应用独特的微流控系统来定量分析白细胞在叠加和动态变化的化学吸引剂场中的迁移行为。此外，我将研究潜在的分子机制，重点是配体诱导的趋化受体信号在免疫细胞迁移中的作用，以响应时空趋化信号。我将使用一种组合的方法，通过实验研究几种突变的非脱敏趋化因子受体在初级白细胞和髓系细胞系迁移中的作用，并通过数学建模和计算机模拟。这项研究将对免疫细胞在复杂的趋化物质领域中的迁移和趋化产生令人兴奋的见解，并将为理解细胞与引导环境之间的复杂相互作用铺平道路。我的研究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。

Immune cell trafficking in tissues is crucial for immune responses and is mediated by various environmental cues such as adhesion molecules and chemoattractants. The focus of past research has been on the roles of individual adhesion molecules and chemoattractants in guiding immune cell trafficking, and the biological mechanisms for cells to detect and respond to simplified non-varying adhesion and migration signals. Because cells are exposed to multiple and spatiotemporally varying directing signals in vivo, understanding immune cell trafficking in complex cellular environment is important for both basic science and clinical research. But very few studies have tried to examine such challenging complexities. The long-term goal of my Discovery program aims at integrating cell biology and immunology approaches, biophysical analysis and novel microfluidic tools to achieve a quantitative and systematic understanding of immune cell trafficking in complex cellular environments. In the first granting period, my focus is on understanding immune cell migration in complex chemoattractant fields. I will apply unique microfluidic systems for quantitative analysis of the migratory behaviours of leukocytes in superimposed and dynamically varying chemoattractant fields. Furthermore, I will investigate the underlying molecular mechanisms with the focus on the role of ligand-induced chemoattractant receptor signalling for immune cell migration in response to spatiotemporal chemotactic signals. I will use a combined approach by experimentally examining the effect of several mutated nondesensitizable chemokine receptors in the migration of both primary leukocytes and myeloid cell lines, and through mathematical modelling and computer simulations. The proposed research will generate exciting insights into immune cell migration and chemotaxis in complex chemoattractant fields and will pave the way for understanding the complex interactions between cells and the guiding environment. My research program will 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.