Resolving innate inflammatory responses to tissue injury and apoptotic cell clearance to develop novel therapeutic strategies for pulmonary diseases

解决对组织损伤和凋亡细胞清除的先天炎症反应，开发肺部疾病的新治疗策略

• 批准号: MR/W019264/1
• 负责人: Will Wood
• 金额: $ 260.4万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW019264%2F1
• 关键词: Resolving; innate; inflammatory; responses; tissue

Inflammation is the body's response to injury, infection or disease. While some conditions (e.g., pneumonia and acute asthma) cause dramatic inflammation, they have the capacity to resolve completely with no residual damage to surrounding tissues. However, in many cases inflammation can become disordered or dysregulated which causes additional damage to tissues of the body. In fact, dysregulated inflammation is responsible for a significant burden of global disease and ill health, especially lung diseases such as acute respiratory distress syndrome, idiopathic pulmonary fibrosis, chronic bronchitis and COVID-19. Over 1 billion people suffer from acute or chronic respiratory diseases, and despite this huge burden of illness, loss of economic productivity and, in many cases, premature death, there is limited or no effective drug therapy for most of these conditions.With MRC support over the last 20 years, we have studied how inflammation resolves and how these processes become dysregulated in chronic inflammatory conditions with the goal of generating new therapies for treating these diseases. In this exciting project, we have two main aims. The first is to understand the machinery that inflammatory cells use to navigate from the bloodstream to the site of inflammation. The second is to determine how ingestion of dead cells generated during disease reprograms macrophages to drive inflammation resolution and complete the tissue repair process. If we can determine the molecules involved in these processes, these could be targeted therapeutically to limit recruitment of inflammatory cells and promote inflammation resolution. To achieve this, we have used one of the simplest model organisms, the common fruit fly, to understand the 'postcode' system used by inflammatory cells for navigation. A major benefit of using the fly as a model system is that it enables us to watch this process of blood cell recruitment in real time within a living animal and rapidly test for new inflammation targets through genetic screening experiments, something not possible in mammals. A 'breakthrough' came when we identified new components of the machinery that scavenger white blood cells (neutrophils and macrophages) use to navigate to inflammatory wounds and for the removal of unwanted dead cells. In this programme of work, we will investigate these novel pathways and use clinically relevant models of human lung disease (in mice) to determine if these pathways control inflammatory cell recruitment in mammals. Complementary analysis of white blood cells isolated from healthy volunteers and from patients with lung diseases will allow us to examine these pathways in human-specific disease contexts.A crucial part of inflammation resolution is the clearance of the inflammatory cells that have been recruited to combat the threat/infection. This process is highly dependent on scavenger immune cells (macrophages) which eat and destroy unwanted inflammatory cells after they have undergone a form of 'silent suicide'. Ingestion of dead inflammatory cells is thought to program macrophages to complete the tissue repair process. However, the molecular pathways that instruct macrophages to perform these functions are very poorly understood. Understanding these pathways could allow us to manipulate them to re-program macrophages in chronic inflammation. So, again, we will use the powerful genetics of the fly to investigate these processes in depth and at scale, then use mouse models to test the candidates we have identified before examining them using white blood cells from individuals with lung disease. Our unique cross-species collaborative approach brings together a team of outstanding scientists that offer an opportunity to understand, at an unprecedented level, the complex machinery controlling inflammation. This information will be critical to design novel therapies for these debilitating and untreatable diseases in the foreseeable future.

炎症是身体对损伤、感染或疾病的反应。虽然某些条件（例如，肺炎和急性哮喘）引起剧烈的炎症，它们有能力完全解决，对周围组织没有残余损伤。然而，在许多情况下，炎症可能变得紊乱或失调，这会对身体组织造成额外的损伤。事实上，炎症失调是全球疾病和健康状况不佳的重要负担，特别是肺部疾病，如急性呼吸窘迫综合征，特发性肺纤维化，慢性支气管炎和COVID-19。超过10亿人患有急性或慢性呼吸道疾病，尽管疾病负担巨大，经济生产力下降，在许多情况下过早死亡，但对大多数这些疾病的药物治疗有限或没有有效的药物治疗。我们研究了炎症如何消退，以及这些过程在慢性炎症条件下如何失调，目的是产生新的治疗方法。来治疗这些疾病。在这个激动人心的项目中，我们有两个主要目标。首先是了解炎症细胞用于从血流导航到炎症部位的机制。第二个是确定在疾病期间产生的死细胞的摄入如何重新编程巨噬细胞以驱动炎症消退并完成组织修复过程。如果我们能够确定参与这些过程的分子，这些分子可以在治疗上靶向限制炎症细胞的募集并促进炎症的消退。为了实现这一点，我们使用了最简单的模式生物之一，普通果蝇，以了解炎症细胞用于导航的“邮政编码”系统。使用果蝇作为模型系统的一个主要好处是，它使我们能够在活体动物中真实的观察血细胞募集的过程，并通过遗传筛选实验快速测试新的炎症靶点，这在哺乳动物中是不可能的。当我们确定了清道夫白色血细胞（中性粒细胞和巨噬细胞）用于导航到炎症伤口和清除不需要的死细胞的机制的新组件时，一个“突破”出现了。在这项工作计划中，我们将研究这些新的途径，并使用临床相关的人类肺部疾病模型（小鼠）来确定这些途径是否控制哺乳动物中的炎症细胞募集。从健康志愿者和肺部疾病患者中分离的白色血细胞的补充分析将使我们能够在人类特定的疾病背景下检查这些通路。炎症解决的一个关键部分是清除已经招募来对抗威胁/感染的炎性细胞。这一过程高度依赖于清道夫免疫细胞（巨噬细胞），它们在经历了一种“沉默自杀”后吃掉并摧毁不需要的炎症细胞。死亡炎症细胞的摄入被认为是巨噬细胞完成组织修复过程的程序。然而，指导巨噬细胞执行这些功能的分子途径知之甚少。了解这些途径可以使我们能够操纵它们来重新编程慢性炎症中的巨噬细胞。因此，我们将再次利用果蝇强大的遗传学来深入和大规模地研究这些过程，然后使用小鼠模型来测试我们已经确定的候选人，然后使用来自肺部疾病患者的白色血细胞进行检查。我们独特的跨物种协作方法汇集了一支杰出的科学家团队，为以前所未有的水平了解控制炎症的复杂机制提供了机会。这些信息对于在可预见的未来为这些使人衰弱和无法治愈的疾病设计新疗法至关重要。