Investigation of Immune Cell Trafficking in Complex Cellular Environment

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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.