Investigation of immune cell trafficking in complex cellular environment

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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.