Autophagy and Crohn's disease: translating genetics to function

自噬和克罗恩病：将遗传学转化为功能

• 批准号: G0800383/1
• 负责人: Dunecan Massey
• 金额: $ 32.04万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0800383%2F1
• 关键词: Autophagy; Crohn; disease; translating; genetics

I aim to investigate the molecular biology of Crohn‘s disease (CD), a chronic debilitating inflammatory bowel condition affecting 100 - 250 per 100,000 people in the UK. Although current understanding suggests that an abnormal response to bacteria living in the gut leads to Crohn‘s inflammation, the mechanisms are not understood - yet understanding this mechanism might permit development of improved treatments or even preventative measures. Recent groundbreaking studies have highlighted two genes involved in autophagy as being significantly associated with CD risk. I will study one of these genes, ATG16L1. Autophagy is a cellular process that degrades unwanted large proteins and other cell structures, and is also implicated in clearance of invasive bacteria. We hypothesise that autophagy is abnormal in CD, leading to defective clearance of bowel pathogens and therefore inflammation. A series of experiments are proposed to test this hypothesis. Using established cell lines from animals and humans, and bowel samples from patients with CD, I will study the effects of the CD-associated variant in ATG16L1 on autophagy, characterize cellular components with which Atg16L1 protein interacts and investigate whether autophagy is generally abnormal in CD even without the currently identified genetic variants.

我的目标是研究克罗恩病（CD）的分子生物学，这是一种慢性使人衰弱的炎症性肠病，在英国每10万人中有100 - 250人受到影响。尽管目前的理解表明，对肠道细菌的异常反应导致了克罗恩病的炎症，但其机制尚不清楚——然而，了解这一机制可能有助于改进治疗方法，甚至采取预防措施。最近的突破性研究强调了两个参与自噬的基因与乳糜泻风险显著相关。我将研究其中一个基因，ATG16L1。自噬是一种降解不需要的大蛋白和其他细胞结构的细胞过程，也与清除侵入性细菌有关。我们假设自噬在乳糜泻中是异常的，导致肠道病原体清除缺陷，从而导致炎症。提出了一系列实验来验证这一假设。利用来自动物和人类的已建立的细胞系，以及来自CD患者的肠道样本，我将研究CD相关的ATG16L1变异对自噬的影响，表征与ATG16L1蛋白相互作用的细胞成分，并研究即使没有目前确定的遗传变异，自噬是否在CD中普遍异常。