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被称为共生菌，它们对人类健康有益，并与我们和平共处。我们的免疫系统以这样一种方式被调节，即容忍这些共生细菌，同时保持对任何试图入侵我们肠道的有害致病菌的快速反应。目前尚不清楚免疫系统是如何区分肠道中的好细菌和坏细菌的，但炎症性肠病（IBD）说明了维持这种平衡的重要性，炎症性肠病是由不适当的免疫反应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），在英国每500人中就有1人患有这两种疾病，目前还没有治愈方法。IBD患者患肠癌的风险也在增加。治疗包括长期服用免疫抑制药物以减轻疾病症状，但这些药物往往有有害的副作用，而且并不总是有效。为了开发新的和改进的治疗方法，更好地了解肠内免疫系统在IBD期间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与IBD的风险增加有关。一些易患IBD的基因变化是与自噬相关的基因，自噬是一种由压力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。本研究的目的是利用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。许多肠道细菌并不直接与免疫系统的白细胞相互作用，而是对排列在肠道表面的上皮细胞产生重要影响。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与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，以及所涉及的途径。收集到的知识可能会为IBD患者带来新的治疗方法，特别是那些携带改变版本的自噬基因的患者。

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.