The uncharted journeys of inflammatory cells and their functional implications

炎症细胞的未知旅程及其功能意义

• 批准号: EP/Y02799X/1
• 负责人: Milka Sarris
• 金额: $ 215.83万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY02799X%2F1
• 关键词: uncharted; journeys; inflammatory; cells; their

Inflammation is a physiological response to injury or harmful agents that ensures tissue defence from invading microbes. This is achieved through inflammatory cells, such as neutrophils and macrophages (also called 'myeloid cells'), which rapidly migrate to damaged loci and execute crucial antimicrobial and tissue repair functions. However, excess or maladaptive inflammation is linked to a range of diseases, from autoimmunity to cancer and neurodegeneration. A key problem in targeting inflammation is our limited understanding of the migration patterns of myeloid cells in vivo. Studies have focused on how these cells reach inflammatory loci, while little is known about their long-term fates. This is important to understand, as increasing evidence reveals that myeloid cells disseminate to other tissues from inflamed lesions, which has implications in resolution of inflammation and host defence.Here, we propose to combine in vivo imaging, genetic manipulations and single-cell transcriptomics in a tractable vertebrate (zebrafish), to elucidate the mechanisms of myeloid cell dissemination, define the identity of disseminating cells and their functional implications. First, we will determine the migration routes of neutrophils and macrophages after microbial encounter, through live imaging and cell tracing, and define the underlying molecular mechanisms, through genetic perturbations. Secondly, we will determine the properties of disseminating inflammatory cells, through single cell transcriptomics, which will generate functional and mechanistic hypotheses for this study and reveal new biomarkers for detection of in vivo inflammatory states. Finally, we will elucidate functions of these cells in immunosurveillance, by tracing the behaviour of individual cells from one infection to the next.This work will fill a major knowledge gap on how inflammatory responses unfold in vivo and shape new ideas for manipulating inflammation towards improved resolution or host defence.

炎症是对损伤或有害试剂的生理反应，其确保组织防御入侵的微生物。这是通过炎症细胞，如中性粒细胞和巨噬细胞（也称为“骨髓细胞”），迅速迁移到受损部位，并执行关键的抗菌和组织修复功能来实现的。然而，过度或适应不良的炎症与一系列疾病有关，从自身免疫到癌症和神经变性。靶向炎症的一个关键问题是我们对体内骨髓细胞迁移模式的理解有限。研究集中在这些细胞如何到达炎症部位，而对其长期命运知之甚少。随着越来越多的证据表明骨髓细胞从炎症病变扩散到其他组织，这对炎症的解决和宿主防御具有重要意义，因此理解这一点很重要。（斑马鱼），阐明骨髓细胞播散的机制，定义播散细胞的身份及其功能意义。首先，我们将通过活体成像和细胞示踪确定微生物相遇后中性粒细胞和巨噬细胞的迁移途径，并通过遗传扰动确定潜在的分子机制。其次，我们将通过单细胞转录组学确定播散性炎症细胞的性质，这将为本研究产生功能和机制假设，并揭示用于检测体内炎症状态的新生物标志物。最后，我们将阐明这些细胞在免疫监视中的功能，通过追踪单个细胞从一种感染到下一种感染的行为，这项工作将填补炎症反应如何在体内展开的主要知识空白，并为操纵炎症改善分辨率或宿主防御形成新的想法。