Autophagy and Crohn's disease: translating genetics to function

我的目标是调查克罗恩病（CD）的分子生物学，这是一种慢性衰弱性炎症性肠病，在英国每10万人中有100 - 250人受到影响。虽然目前的理解表明，对肠道细菌的异常反应会导致克罗恩病炎症，但其机制尚不清楚-但了解这种机制可能有助于开发改进的治疗方法甚至预防措施。最近的突破性研究强调了两个参与自噬的基因与CD风险显著相关。我将研究这些基因之一，ATG 16 L1。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，也涉及入侵细菌的清除。我们假设自噬在CD中是异常的，导致肠道病原体的清除缺陷，从而导致炎症。提出了一系列实验来验证这一假设。使用从动物和人类建立的细胞系，以及CD患者的肠道样本，我将研究CD相关的ATG 16 L1变体对自噬的影响，表征与Atg 16 L1蛋白相互作用的细胞成分，并调查自噬在CD中是否普遍异常，即使没有目前确定的遗传变异。

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.