Cell-type specific functions of autophagy in intestinal physiology and pathology

生活在我们肠道中的绝大多数细菌，称为细菌，对人类健康有益，并与我们和平共处。我们的免疫系统以这样一种方式进行调节，以耐受这些肠道细菌，同时保持对任何试图入侵我们肠道的有害病原菌的快速反应。目前尚不清楚免疫系统如何能够区分肠道中的好细菌和坏细菌，但维持这种平衡的重要性通过炎症性肠病（IBD）来说明，炎症性肠病是由针对肠道细菌的免疫反应的不适当激活引起的肠道慢性衰弱性疾病。IBD包括克罗恩病（CD）和溃疡性结肠炎（UC），这两种疾病共同影响英国约1/500的人，目前尚无治愈方法。IBD患者患肠癌的风险也增加。治疗包括长期服用免疫抑制药物以减轻疾病症状，但这些药物通常具有有害的副作用，并不总是有效的。为了开发新的和改进的治疗方法，更好地了解IBD期间肠道免疫系统如何发生故障是必要的。IBD患者的遗传学研究表明，参与细菌识别和控制的基因的改变版本与IBD风险增加有关。一些易患IBD的遗传变化与自噬相关，自噬是一种由应激或饥饿诱导的细胞生存反应。然而，最近的研究表明，自噬蛋白也参与了对细菌感染的免疫防御，本研究的目的是使用IBD小鼠模型来研究自噬蛋白在控制肠道炎症中的作用。第二个关键目标是更好地了解自噬蛋白在肠道不同类型细胞中的免疫功能。许多肠道细菌不直接与免疫系统的白色血细胞相互作用，而是对肠道表面的上皮细胞有重要影响。反过来，上皮细胞可以影响宿主免疫细胞的行为。因此，我们的目标是使用在肠上皮细胞或宿主免疫细胞中缺乏某些自噬基因的转基因小鼠，这些实验将帮助我们确定自噬蛋白如何有助于控制肠道炎症反应以及宿主细胞和肠道细菌之间的相互作用。我们还希望确定自噬蛋白介导其作用的肠细胞，以及相关的途径。所收集的知识可能会为IBD患者带来新的治疗方法，特别是那些携带自噬基因改变的患者。

The vast majority of bacteria that live in our intestine, termed commensals, are beneficial for human health and co-exist peacefully with us. Our immune system is regulated in a such a way as to tolerate these commensal bacteria, while remaining poised to rapidly respond to any harmful pathogenic bacteria that try to invade through our intestine. It is not clear how the immune system is able to discriminate between good and bad bacteria in our guts, but the importance of maintaining this balance is illustrated by the inflammatory bowel diseases (IBD), chronic debilitating disorders of the intestine caused by inappropriate activation of immune response against commensal bacteria. IBD encompass Crohn's disease (CD) and ulcerative colitis (UC), which together affect around 1 in 500 people in the UK and currently there is no cure. IBD patients are also at increased risk of developing bowel cancer. Treatment involves long term administration of immune suppressive drugs to reduce the symptoms of disease, but these often have harmful side effects and are not always effective. A better understanding of how the immune system malfunctions in the intestine during IBD is necessary in order to develop new and improved therapies.Genetic studies in IBD patients have indicated that altered versions of genes involved in bacterial recognition and control are associated with an increased risk of IBD. Several genetic changes that predispose to IBD are in genes associated with autophagy, a cellular survival response that is induced by stress or starvation. However, recent studies have shown that autophagy proteins are also involved in immune defense against bacterial infection.The aim of this study is to use mouse models of IBD to to investigate the role of autophagy proteins in controlling inflammation in the intestine. The second key objective is to better understand the immune functions of autophagy proteins in different types of cells in the intestine. Many intestinal bacteria do not directly interact with the white blood cells of the immune system, but instead have important effects on the epithelial cells that line the surface of the intestine. In turn, the epithelial cells can influence the behaviour of the host immune cells. Therefore, we aim to use genetically-modified mice that lack certain autophagy genes either in the intestinal epithelial cells or in the host immune cells.These experiments will help us define how autophagy proteins contribute to the control of inflammatory responses in the intestine and to the interactions between host cells and intestinal bacteria. We also hope to identify the intestinal cells in which autophagy proteins mediate their effects, as well as the pathways involved. The knowledge gleaned may lead to novel therapies for patients with IBD, especially for those who carry altered versions of autophagy genes.