Characterising neutrophil reverse migration using wet and dry experimentation

使用湿法和干法实验表征中性粒细胞逆向迁移

• 批准号: 2259634
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2259634
• 关键词: Characterising; neutrophil; reverse; migration; using

Neutrophils are the predominant type of leukocyte in humans and form an integral part of the innate immune system. Upon activation, they move to the site of infection or injury, following gradients of chemokines in a process called chemotaxis. Once there, they perform effector functions (e.g. phagocytosis, release of ROS) before dying by apoptosis. Neutrophil reverse migration, or retrograde chemotaxis, is the movement away from the site of infection or injury and opposite to the attracting chemokine gradient. It has been described in vitro and in vivo, and is contrary to existing dogma of neutrophil behaviour. The process may be involved in inflammation resolution, but has been shown to have a pathologic aspect, promoting inflammation at distal sites such as the lungs. It is thought it could be implicated in chronic inflammatory diseases such as rheumatoid arthritis and COPD.This project will investigate the molecular mechanisms controlling neutrophil reverse migration by combining computational modelling with wet lab methods. Basal and post-migrated neutrophils will be examined using bespoke chemotaxis assays optimised for this project. Their chemotactic behaviour and differential chemokine and receptor expression will be compared. Computational modelling will be used to find and expand ways in which metabolism of chemokines and other attractive molecules can turn them from attractants into repellents and be used to define more informative experimental set-ups, the results of which will in turn be used to test and further refine the model. There are several possibilities to be addressed: Does chemoattractant break-down mediate reverse migration? Do chemoattractants turn into chemorepellents? Does reverse migration involve receptor desensitization? Do neutrophils change once they have been recruited to a site of infection? This project will work towards identifying how neutrophil reverse migration could be therapeutically targeted.

中性粒细胞是人类白细胞的主要类型，并且形成先天免疫系统的组成部分。一旦被激活，它们就会沿着趋化因子的梯度移动到感染或损伤部位，这一过程称为趋化性。一旦存在，它们在通过凋亡死亡之前执行效应器功能（例如吞噬作用、ROS的释放）。中性粒细胞反向迁移或逆行趋化性是远离感染或损伤部位的运动，与吸引趋化因子梯度相反。它已在体外和体内进行了描述，并与现有的中性粒细胞行为的教条相反。该过程可能涉及炎症消退，但已显示具有病理学方面，促进远端部位（如肺部）的炎症。它被认为可能与慢性炎症性疾病如类风湿性关节炎和COPD有关。本项目将通过结合计算模型和湿实验室方法来研究控制中性粒细胞反向迁移的分子机制。将使用针对本项目优化的定制趋化性试验检查基础和迁移后中性粒细胞。将比较它们的趋化行为和差异趋化因子和受体表达。计算建模将用于寻找和扩展趋化因子和其他有吸引力的分子的代谢可以将它们从引诱剂转变为排斥剂的方法，并用于定义更多信息的实验设置，其结果将反过来用于测试和进一步完善模型。有几种可能性需要解决：化学引诱物分解介导的反向迁移？化学引诱物会变成化学排斥物吗？逆迁移是否涉及受体脱敏？中性粒细胞一旦聚集到感染部位会发生变化吗？该项目将致力于确定如何以中性粒细胞反向迁移为治疗目标。