Deciphering cathelicidin-induced IL-17F production in the intestine

在这个项目中，我们正在研究白细胞在肠道中的行为，以及是什么控制了它们的行为。这很重要，因为这些细胞是炎症性肠病（包括克罗恩病和溃疡性结肠炎）的关键驱动因素。我们正试图找出是什么让这些细胞在某些情况下有害，而在另一些情况下有益。我们对有益细胞和有害细胞进行分类的方法之一是它们产生的蛋白质类型，特别是称为细胞因子的蛋白质。细胞因子是重要的指令信号，它告诉细胞去哪里以及如何对感染作出反应。在某些情况下，细胞因子具有保护作用，而在其他情况下，它们可能具有破坏性——它们会使细胞反应过于强烈，或者移动到错误的位置，从而导致像肠道这样的组织受损。在这里，我们正在研究一种特殊的细胞因子，IL-17F。我们知道它存在于肠道中，但我们不知道它是如何产生的，是什么控制着它，也不知道它在疾病期间有什么作用。我们不知道它对人类IBD是有益还是有害，尽管在小鼠中，它似乎对驱动疾病非常重要，因此是一种有希望的治疗候选者。我们认为IL-17F的一个关键驱动因子是一种在感染过程中释放的肽，它可以杀死细菌、病毒和真菌。这种抗菌肽被称为抗菌肽，在肠道中以高浓度表达。现在，我们认为它导致IL-17F的表达这是肠道疾病开始的方式之一。在这个项目中，我们将研究：cathelicidin如何导致IL-17F表达，IL-17F在人体肠道中的表达位置，以及cathelicidin诱导的IL-17F对肠道疾病的发展是否重要。我们将通过三种类型的实验来做到这一点。首先，我们将使用从健康人群和IBD患者身上收集的样本。这些样本包括血液、粪便和从小肠和结肠中提取的活组织检查。我们将观察这些样本，并计算出IL-17F的含量，它的确切位置，以及哪些细胞会产生它。接下来，我们将在实验室的培养皿中观察来自老鼠和健康人血液的细胞。我们将找出驱动白细胞中IL-17F表达的触发因素，以及cathelicidin的重要性。最后，我们将在小鼠身上使用IBD模型——我们可以看看当它们没有IL-17F或抗菌肽时，它们的肠道会发生什么。我们将在爱丁堡大学的炎症研究中心进行所有这些实验。将有三名工作人员参与其中：一名博士后进行实验室实验，一名生物信息学专家将帮助处理该项目涉及的大量数据，一名首席研究员将负责该项目，并负责数据管理、安全、保存记录和发布结果。该项目将产生三个重要成果。它将首次全面描绘出IL-17F在人类肠道中的表达方式，这对于我们试图更详细地了解健康和受损肠道是绝对必要的。研究cathelicidin如何特异性诱导IL-17F，这是一个有趣的免疫学新课题。它还将确定cathelicidin诱导IL-17F是否是我们开发IBD新疗法的目标。这项工作将对研究细胞因子和抗菌肽的免疫学家、医生和IBD患者感兴趣。

In this project we are investigating how white blood cells behave in the intestine, and what controls their behaviour. This is important, because these cells are the key drivers behind inflammatory bowel diseases (IBD) which include Crohn's disease and Ulcerative Colitis. We are trying to work out what makes these cells damaging in some situations and helpful in others. One of the ways we categorise helpful and damaging cells is the type of proteins they produce - particularly proteins called cytokines. Cytokines are important instruction signals which tell cells where to go and how to react to infection. In some cases cytokines are protective, and in others they can be damaging - they can make the cells react too strongly, or to move into the wrong place, which causes damage to tissue like the intestine. Here, we are investigating one particular cytokine, IL-17F. We know that this is present in intestines but we don't really know how it is made, what controls it, nor what it does during disease. We don't know whether it is helpful or damaging in human IBD, although in mice it seems to be very important for driving disease and is therefore a promising therapeutic candidate.We propose that a key driver of IL-17F is a peptide which is released during infection and which kills bacteria, viruses and fungi. This antimicrobial peptide, called cathelicidin, is expressed at high concentration in the intestine. Now, we think that it causes IL-17F to be expressed and that this is one of the ways in which bowel disease begins. In this project we will work out: how cathelicidin causes IL-17F to be expressed, where IL-17F is expressed in the human bowel, and whether cathelicidin-induced IL-17F is important for the development of bowel disease.We will do this through three types of experiments. Firstly, we will use samples that we have collected from healthy people and from patients with IBD. These samples include blood, faeces, and biopsies taken from their small intestine and colon. We will look at these samples and work out how much IL-17F is present, exactly where it is, and which cells make it. Next, we will look at cells in dishes in the lab - from mice and from blood taken from healthy people. We will work out the triggers that drive IL-17F expression from white blood cells and how cathelicidin may be important. Finally, we will usemodels of IBD in mice - we can look at what happens in their intestines when they do not have IL-17F, or cathelicidin. We will carry out all of these experiments at the Centre for Inflammation Research at the University of Edinburgh. Three members of staff will be involved: a postdoctoral fellow to carry out the lab experiments, a bioinformatics specialist who will help crunch the enormous amounts of data this project will involve, and a principal investigator who will run the project and be responsible for data management, safety, keeping records and publishing results.This project will have three important outcomes. It will fully map how IL-17F is expressed in the human intestine for the first time, which is absolutely necessary as we try to understand healthy and damaged intestines in greater detail. It will work out how cathelicidin specifically induces IL-17F, which is interesting and novel immunologically. It will also determine whether this induction of IL-17F by cathelicidin is something we could target as we try to develop novel therapies for IBD. This work will be of interest to immunologists working with cytokines and antimicrobial peptides, to doctors, and to patients with IBD.