Leukocyte guidance and gradient interpretation in vivo

体内白细胞引导和梯度解释

• 批准号: MR/L019523/1
• 负责人: Milka Sarris
• 金额: $ 123.64万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL019523%2F1
• 关键词: Leukocyte; guidance; gradient; interpretation; vivo

Our immune system is designed to protect us from infections. For any immune response to occur, white blood cells (leukocytes) need to exit the blood stream and then navigate within tissues in order to find and eliminate invading microbes. This process absolutely relies on their ability to accurately interpret guidance signals produced within tissues. Any malfunction in this process can be the basis of inflammatory diseases (such as allergy, asthma, arthritis and various conditions ending with the suffix '-itis') or insufficient responses to infection (for example in immuno-compromised patients with leukocyte migration defects, such as 'WHIM syndrome' patients). For this reason, manipulating leukocyte navigation for treating inflammatory diseases is a major biomedical target.This target has yet to be met, as we still have little understanding of how leukocytes are guided within the body. Although many types of guidance cues have been identified over the past decades, their actual mode of action and interpretation by leukocytes are poorly understood. If we can understand this, we can be in a much better position of designing effective and selective treatments for inflammatory diseases.I have set up a model system in which we can directly visualize how leukocytes are guided towards infected tissues and dissect the genes and mechanisms that underlie this process. For this I have taken advantage of the zebrafish model, as it is optically transparent, allowing us to easily monitor leukocyte migration, and genetically tractable, allowing us to uncover the underlying genetic mechanisms. Using this unique model system, I have so far discovered that certain guidance cues produced at sites of infection - small proteins called 'chemokines' - need to interact with complex sugars in the tissue environment in order to accurately guide the migration of leukocytes. This has many implications and fundamentally changes our understanding of how chemokines operate. In my proposed plan I intend to elucidate further the mechanism of action of chemokines. We (myself, a research assistant and a team of collaborators with complementary expertise) will investigate how sugars of the tissue environment change the signaling properties of chemokines and how exactly leukocytes process this information into directed movement. We will also expand this approach to other important guidance signals, beyond chemokines. These studies will provide a better understanding of how leukocytes 'read' guidance signals so as to navigate correctly in the body, which can ultimately open new avenues for treating inflammatory diseases.

我们的免疫系统旨在保护我们免受感染。对于任何免疫反应的发生，白色血细胞（白细胞）需要离开血流，然后在组织内导航，以发现和消除入侵的微生物。这个过程完全依赖于他们准确解释组织内产生的引导信号的能力。这个过程中的任何功能障碍都可能是炎症性疾病（如过敏、哮喘、关节炎和以后缀“-itis”结尾的各种病症）或对感染反应不足（例如，在具有白细胞迁移缺陷的免疫受损患者中，如“WHIM综合征”患者）的基础。因此，操纵白细胞导航以治疗炎症性疾病是一个主要的生物医学目标。这个目标尚未实现，因为我们仍然对白细胞如何在体内被引导知之甚少。尽管在过去的几十年中已经确定了许多类型的指导线索，但对它们的实际作用模式和白细胞的解释知之甚少。如果我们能理解这一点，我们就能更好地设计有效的、选择性的炎症性疾病治疗方法。我建立了一个模型系统，在这个系统中，我们可以直接可视化白细胞是如何被引导到感染组织的，并剖析了这个过程背后的基因和机制。为此，我利用了斑马鱼模型，因为它是光学透明的，使我们能够很容易地监测白细胞迁移，并在遗传上易于处理，使我们能够揭示潜在的遗传机制。使用这个独特的模型系统，到目前为止，我已经发现，在感染部位产生的某些指导线索-称为“趋化因子”的小蛋白质-需要与组织环境中的复合糖相互作用，以准确地指导白细胞的迁移。这有许多影响，并从根本上改变了我们对趋化因子如何运作的理解。在我提出的计划中，我打算进一步阐明趋化因子的作用机制。我们（我自己，一个研究助理和一个具有互补专业知识的合作者团队）将研究组织环境中的糖如何改变趋化因子的信号传导特性，以及白细胞如何准确地将这些信息处理成定向运动。我们还将把这种方法扩展到其他重要的指导信号，而不仅仅是趋化因子。这些研究将更好地了解白细胞如何“读取”引导信号，以便在体内正确导航，这最终可以为治疗炎症性疾病开辟新的途径。

项目成果

Chemokine receptor trafficking coordinates neutrophil clustering and dispersal at wounds in zebrafish

趋化因子受体运输协调斑马鱼伤口处中性粒细胞的聚集和分散

• DOI: 10.17863/cam.59968
• 发表时间: 2019
• 作者: Coombs C

Neutrophil motion in numbers: How to analyse complex migration patterns.

中性粒细胞的数量运动：如何分析复杂的迁移模式。

• DOI: 10.1016/j.cdev.2021.203734
• 发表时间: 2021
• 期刊: Cells & development
• 影响因子: 3.9
• 作者: Georgantzoglou A

A two-step search and run response to gradients shapes leukocyte navigation in vivo.

• DOI: 10.1083/jcb.202103207
• 发表时间: 2022-08-01
• 期刊: The Journal of cell biology