How Paneth cells become a site for intestinal inflammation

英国每300人中就有1人患有克罗恩病（CD），主要在年轻人中引起严重的复发性腹部症状，扰乱了教育、工作和家庭生活。许多患者需要类固醇、长期免疫抑制剂和抗体治疗，75%的患者最终需要大手术+/-回肠造口术。克罗恩病的病因尚不清楚，但自2007年以来，在了解其遗传基础方面取得了巨大进展。特别是自噬过程中的缺陷（细胞成分降解和再循环的细胞途径），在回肠CD的发展中得到了强调。由Kaser实验室率先开展的工作集中在Paneth细胞的作用上，并揭示了这些细胞作为肠道炎症的潜在发起者。Paneth细胞是肠道分泌细胞，它调节着生活在肠道中的数百万细菌和我们免疫系统之间的界面。在小鼠模型中，具有与人类相同的自噬受损遗传风险的细胞在肠道微生物群存在的情况下变得紧张，并且发现这些动物出现了具有克罗恩病许多特征的回肠炎症。本研究计划的主要目的是：1。为了扩大我们对Paneth细胞参与的关键炎症途径的认识。了解下游的免疫细胞是如何受到影响的。为了确定是否有相似的生物标记物可以根据这种疾病机制对乳清患者进行分层，这项研究将在剑桥大学阿登布鲁克医院的Kaser实验室进行。使用上述小鼠模型，Paneth细胞将被分离出来，以研究导致特定免疫细胞激活并最终导致回肠炎症的炎症机制。在此之后，将对患有乳糜泻和类似基因损伤的患者的人体活检进行调查，看看这些观察结果是否重演。这项研究将由胃肠病学专业注册医师Joya Bhattacharyya博士进行，他从临床培训中抽出时间进行研究培训并攻读博士学位。这项研究计划的首要主题是使用小鼠模型来获得克罗恩病病因的机制洞察，从而使我们了解遗传风险因素如何导致肠道炎症。这一系列的研究可能最终确定特定的生物标志物，可用于针对那些最有可能从中受益的患者的靶向治疗。

Crohn's disease (CD) affects 1 in 300 of the UK population, causing severe recurrent abdominal symptoms mainly in young adults - disrupting education, jobs and family life. Many patients require steroids, long-term immunosuppressants and antibody therapies and 75% ultimately require major surgery +/- ileostomy. The cause of Crohn's remains unknown but since 2007 there has been huge progress in understanding its genetic basis. In particular defects in a process called autophagy (a cellular pathway for the degradation and recycling of cellular components), have been highlighted in the development of ileal CD. Work pioneered by the Kaser lab has focused attention on the role of the Paneth cell and revealed these as potential originators of intestinal inflammation. Paneth cells are intestinal secretory cells that regulate the interface between the millions of bugs that live in the gut and our immune system. In a mouse model cells with the same human genetic risk for impaired autophagy become stressed in the presence of intestinal microbiota and the animals were found to develop ileal inflammation with many of the features of Crohn's disease. The key aims of this research proposal are 1. To extend our knowledge of the key inflammatory pathways that Paneth cells engage 2. Tounderstand how and which immune cells are affected downstream of this3. To identify if there are similar biomarkers allowing CD patients to be stratified based on this disease mechanismThis research will be undertaken in the Kaser laboratory at Addenbrooke's Hospital in Cambridge. Using the mouse model described above Paneth cells will be isolated to study what inflammatory mechanisms are engaged that result activation of specific immune cells and ultimately in ileal inflammation. Following this, human biopsies from patients with CD and similar genetic impairment will be investigated to see if these observations are recapitulated.The research will be conducted by Dr Joya Bhattacharyya, a specialist registrar in gastroenterology who has taken time out of clinical training to undertake research training and pursue a PhD. The overarching theme of this research proposal is to use a mouse model to gain mechanistic insight into the cause of Crohn's disease, thereby allowing us to understand how genetic risk factors result in intestinal inflammation. This line of research may ultimately identify specific biomarkers that can be used to target therapies towards those patients most likely to benefit from them.