Investigation of Immune Cell Trafficking in Complex Cellular Environment

复杂细胞环境中免疫细胞贩运的研究

• 批准号: RGPIN-2014-04789
• 负责人: Lin, Francis
• 金额: $ 2.99万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=688285
• 关键词: Investigation; Immune; Cell; Trafficking; Complex

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.

组织中的免疫细胞运输对于免疫应答至关重要，并且可以通过各种环境引导线索（例如化学浓度梯度和电场）来引导。虽然化学梯度引导的细胞迁移（即趋化性）是一个研究得很好的生物学过程，但免疫细胞如何响应复杂的化学引诱物场而迁移还没有很好地理解，这代表了体内的现实情况。此外，电场引导的免疫细胞迁移（即趋电性）的机制尚未明确定义。由于化学和电场可以在体内共存并以组合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贩运的定量和系统性了解。在过去的五年里，我的实验室在确定共存化学引诱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趋电性及其与趋化性的相互作用方面取得了进展。基于这一进展，在未来五年内，我们将进一步研究复杂电化学引导环境中免疫细胞迁移和贩运的引导机制。在一个方向上，我们将进一步探索在复杂的趋化因子场中免疫细胞迁移的组合引导机制，重点关注趋化因子梯度状态和分布的影响以及趋化因子受体脱敏的作用。我们将使用微流体装置测试在不同化学引诱物梯度配置中表达突变的化学引诱物受体的原代免疫细胞和细胞转染物的迁移。此外，我们将进一步开发定量模型，以补充实验研究。在另一个方向，我们将专注于研究化学和电引导信号在引导免疫细胞迁移中的竞争。我们将采用微流体设备，可以产生高度控制的重叠化学梯度和电场，用于细胞迁移分析。此外，我们将探索几种可能的潜在信号机制，包括受体电迁移和钙信号使用相结合的实验和建模方法。我希望我的发现计划能对组织中免疫细胞运输的生物学做出重大贡献，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。此外，我的探索计划将为一系列HQP创造高质量的跨学科培训机会。