MICA: Tissue ecology in IBD-development and pathophysiological function

MICA：IBD 发展和病理生理功能中的组织生态学

• 批准号: MR/W025981/1
• 负责人: Fiona Powrie
• 金额: $ 225.29万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW025981%2F1
• 关键词: MICA; Tissue; ecology; IBD; development

The intestine is one of the largest immune organs in the body. In health, a complex communication network ensures intestinal immune cells peacefully co-exist with the large number of microbes that inhabit the gut. To maintain this tolerance, epithelial cells that form the intestinal wall, underlying immune cells and fibroblasts constantly process signals from their environment. These signals can originate from the sensing of bacteria, or from molecules called cytokines that cells use to communicate with each other. Long-term disruption to any of these communication pathways can result in the development of chronic inflammation and disease.Inflammatory bowel diseases (IBDs) are characterised by a damaging inflammation of the intestinal wall. There is no cure for IBD and patients go through unpredictable periods of relapse and remission. Genes, diet and other environmental factors result in a host-microbial dialogue that is highly individualised across patients. As a consequence, IBDs are highly variable in terms of disease behaviour, location and the response to therapies. Personalised therapies, however, are not standard practise for IBD, reflected by high failure rates of each of the different drugs, with more than 1 out of 2 patients not responding to treatment in the long-term. In recent studies, we grouped patients with IBD that do not respond well to current therapies based on their cellular and molecular characteristics or 'pathotype'. In the proposed programme, we will characterise these IBD pathotypes in more detail and discover new ones. We will examine the cell types, microbes, signalling molecules and clinical features of each pathotype and develop mouse models that accurately reflect disease in these different patient groups. Using these mouse models, we will look at how cytokines control communication between epithelial cells, immune cells and fibroblasts to contribute to disease. Information gained from these studies will be used to design and test candidate therapies. Finally, we will validate the most promising drug candidates in experiments using gut tissues derived from IBD patients belonging to the different pathotypes. Overall, we will generate new information about of the diversity of pathologic processes that drive inflammation in the intestine that can be used as a biological evidence-based guide for improving and personalized therapies in IBD.

肠道是人体最大的免疫器官之一。在健康方面，一个复杂的通信网络确保肠道免疫细胞与栖息在肠道中的大量微生物和平共处。为了维持这种耐受性，形成肠壁的上皮细胞、免疫细胞和成纤维细胞不断处理来自环境的信号。这些信号可以来自细菌的感知，或者来自细胞用来相互交流的细胞因子分子。长期中断这些通信途径中的任何一个都可能导致慢性炎症和疾病的发展。炎症性肠病（IBD）的特征是肠壁的破坏性炎症。IBD无法治愈，患者会经历不可预测的复发和缓解期。基因、饮食和其他环境因素导致宿主-微生物对话，这种对话在患者中高度个性化。因此，IBD在疾病行为、位置和对治疗的反应方面具有高度可变性。然而，个性化治疗并不是IBD的标准做法，这反映在每种不同药物的高失败率上，超过1/2的患者对长期治疗没有反应。在最近的研究中，我们根据其细胞和分子特征或“病理类型”将对当前治疗反应不佳的IBD患者分组。在拟议的计划中，我们将更详细地分析这些IBD病理类型并发现新的类型。我们将检查每种病理类型的细胞类型，微生物，信号分子和临床特征，并开发准确反映这些不同患者群体疾病的小鼠模型。使用这些小鼠模型，我们将研究细胞因子如何控制上皮细胞，免疫细胞和成纤维细胞之间的通讯，以促进疾病。从这些研究中获得的信息将用于设计和测试候选疗法。最后，我们将使用来自不同病理类型的IBD患者的肠道组织在实验中验证最有希望的候选药物。总的来说，我们将产生关于驱动肠道炎症的病理过程多样性的新信息，这些信息可用作改善IBD和个性化治疗的生物学循证指南。