Investigation of immune cell trafficking in complex cellular environment

免疫细胞在组织中的运输对于免疫应答至关重要，并且由各种环境因素如粘附分子和化学引诱物介导。过去的研究重点是单个粘附分子和化学引诱物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非变化粘附和迁移信号的生物学机制。由于细胞在体内暴露于多种时空变化的定向信号，因此了解复杂细胞环境中的免疫细胞运输对于基础科学和临床研究都很重要。但很少有研究试图研究这种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，生物物理分析和新型微流体工具，以实现对复杂细胞环境中免疫细胞贩运的定量和系统性理解。在第一个授予期，我的重点是了解免疫细胞迁移在复杂的化学引诱领域。我将应用独特的微流控系统定量分析白细胞在叠加和动态变化的化学引诱物领域的迁移行为。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传导的作用，免疫细胞迁移的时空趋化信号。我将使用一种综合的方法，通过实验研究几种突变的非脱敏趋化因子受体在原代白细胞和骨髓细胞系迁移中的作用，并通过数学建模和计算机模拟。这项研究将对复杂化学引诱物领域中的免疫细胞迁移和趋化性产生令人兴奋的见解，并为理解细胞与引导环境之间的复杂相互作用铺平道路。我的研究计划将大大有助于组织中免疫细胞贩运的生物学，这将与广泛的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.