Manipulating autophagy and related pathways to optimise intestinal Treg cell function and ameliorate intestinal inflammation.

人类的肠道承载着大量的细菌，它们与我们有益地共存——我们为它们提供空间和营养，而它们帮助防止有害细菌的感染。这种共存是可能的，因为我们的免疫系统学会了容忍这些有益的细菌，同时对到达我们肠道的有害细菌保持警惕。然而，在一些个体中，这种耐受性停止工作，免疫系统攻击有益细菌。这可能导致炎症性肠病（IBD）的发展，这是肠道的慢性炎症性疾病。IBD的病因尚不完全清楚，目前还没有治愈方法，但治疗包括长期服用抑制免疫系统的药物。IBD的症状和治疗中使用的药物的副作用对患者的生活质量有不利影响，在许多情况下，需要手术切除受影响的肠道区域。此外，个体IBD患者的病程和对当前治疗的反应差异很大。为了开发新的和改进的治疗方法，更好地了解IBD期间肠道免疫系统是至关重要的。众所周知，IBD具有遗传成分，并且更有可能在特定基因发生变化的人群中发展。这些基因中有几个对自噬过程很重要，自噬是细胞内降解和回收受损成分的关键途径。我们小组和其他人的研究表明，白细胞的一个重要子集T细胞，以及排列在人体肠道上的上皮细胞，需要自噬才能发挥最佳功能。T细胞的一种亚型，被称为调节性T细胞，对于保持人体肠道的耐受性至关重要，它们在肠道中出现的频率很高。然而，我们发现，如果没有自噬过程，它们在肠道中会大大减少，并且功能受损。在这个项目中，我们的目标是更好地了解自噬如何控制肠道中调节性T细胞的存活和功能。我们将使用一种称为生物信息学的分析来比较数千个正常和自噬缺陷的调节性T细胞。这将使我们能够识别由自噬控制的调节性T细胞中的关键分子和途径。我们将在实验室中培养调节性T细胞，以检查这些分子和途径的操纵（例如使用药物）如何影响调节性T细胞的发育和存活。我们将利用我们的结果对自噬缺陷调节性T细胞进行改变，以规避其缺陷并恢复其功能。在项目的最后一部分，我们将使用IBD小鼠模型来研究诱导自噬是否可以预防或治愈肠道炎症。由于自噬是一个发生在所有细胞中的过程，我们将使用转基因小鼠，其中特定类型的细胞呈现自噬缺陷，以帮助我们确定自噬如何影响疾病的不同阶段。总的来说，我们的项目将帮助我们设计新的方法来靶向自噬过程，以减轻肠道中的有害炎症。这可能最终导致IBD患者的新治疗方法，特别是那些与自噬相关的基因发生改变的患者。

The human gut hosts a huge number of bacteria which live in a beneficial co-existence with us - we provide space and nutrients for them, while they help prevent infection by harmful bacteria. This co-existence is possible because our immune system learns to tolerate these beneficial bacteria, while remaining alert towards harmful bacteria that reach our intestine. However, in some individuals this tolerance stops working and the immune system attacks the beneficial bacteria. This can lead to the development of inflammatory bowel diseases (IBD), which are chronic inflammatory disorders of the gut. The causes of IBD are not fully understood and there is currently no cure, but treatment involves long-term administration of drugs which suppress the immune system. The symptoms of IBD and the side-effects of the drugs used in treatment have detrimental effects on patients' quality of life and, in many cases, surgery is required to remove affected regions of the gut. In addition, the course of disease and response to current therapies varies widely in individual IBD patients. To develop new and improved therapies a better understanding of the immune system in the intestine during IBD is crucial. It is known that IBD has a genetic component and is more likely to develop in humans who have changes to specific genes. Several of these genes are important for a process called autophagy - a key pathway used to degrade and recycle damaged components inside our cells. Studies from our group and others have shown that an important subset of white blood cells called T cells, as well as the epithelial cells that line the human gut, require autophagy for their optimal function. A subtype the T cells, called regulatory T cells, are essential for preserving tolerance in the human gut, where they are present in high frequencies. However, we have found that they are greatly reduced in the gut and are impaired in their function if the process of autophagy is absent. In this project, we aim to better understand how autophagy controls the survival and function of regulatory T cells in the gut. We will use a type of analysis called bioinformatics to compare thousands of normal and autophagy-deficient regulatory T cells. This will allow us to identify key molecules and pathways in regulatory T cells that are controlled by autophagy. We will grow regulatory T cells in the laboratory to check how manipulation of these molecules and pathways (e.g. using drugs) affects the development and survival of regulatory T cells. We will use our results to make alterations to the autophagy-deficient regulatory T cells to circumvent their defects and restore their function. In the final part of the project, we will use mouse models of IBD to investigate if inducing autophagy can prevent or cure intestinal inflammation. As autophagy is a process that occurs in all cells, we will use genetically modified mice in which specific types of cells are rendered autophagy-deficient to help us define how autophagy can affact different stages of disease.Overall, our project will help us to devise new ways to target the process of autophagy to alleviate harmful inflammation in the gut. This may eventually lead to new treatments for IBD patients, especially those who have alterations in genes that are linked to autophagy.