Decoding the Obese Duodenum

解码肥胖十二指肠

• 批准号: MR/Y013980/1
• 负责人: Gavin Bewick
• 金额: $ 147.22万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY013980%2F1
• 关键词: Decoding; Obese; Duodenum

Obesity is a major health problem. Understanding how obesity causes diseases like diabetes and liver problems will help the design of new treatments. The goal of this project is to understand how the first part of the small intestine, called the duodenum, changes when someone becomes obese, and how this might drive diseases related to obesity. Little is known about these processes at present. Our early data suggests that obesity causes changes in the duodenum which can cause inflammation and compromise the function of the duodenum as a protective barrier. These changes in the duodenum may further worsen metabolism and increase the damage caused by obesity to metabolically important organs such as the liver. By studying how these changes occur and what they do to the duodenum, we hope to understand how they exacerbate the health problems associated with obesity and identify new targets for drugs to treat these diseases. To achieve this, we will:Create a detailed map of the differences in the duodenum of lean (non-obese) and obese individuals. We will look at the different types of cells and their activities, as well as the bacteria living in the duodenum. By comparing lean and obese people, we will determine how obesity affects the duodenum and find important pathways that contribute to metabolic problems.We will then use this information to investigate how these changes affect the function of the duodenum. To do this, we will grow small models of the duodenum called organoids using human cells in the laboratory. These organoids will help us understand how the changes in the duodenum affect the gut's ability to keep out harmful substances, how the cells renew themselves, and how these changes might contribute to metabolic problems. We will then test whether the same mechanisms worsen metabolism in mice as they become obese. Finally, we will explore whether improving the health of the duodenum in obesity can help reduce the negative effects of obesity on metabolism. Using the organoids, we will test different treatments to find which is most effective. We will then give this treatment to mice developing obesity see if it improves their metabolism, including how they process sugar and the level of damage and inflammation in their tissues.This programme of work will discover how the duodenum is affected by obesity, determine if these changes cause further health problems, and establish whether treating or preventing these changes may help people with metabolic diseases.

肥胖是一个主要的健康问题。了解肥胖是如何引起糖尿病和肝脏问题等疾病将有助于设计新疗法。该项目的目的是了解小肠的第一部分（称为十二指肠）是如何在某人变成肥胖时会发生变化的，以及这可能会导致与肥胖有关的疾病。目前对这些过程知之甚少。我们的早期数据表明，肥胖会导致十二指肠变化，这可能会导致炎症并损害十二指肠作为保护屏障的功能。十二指肠的这些变化可能会进一步恶化新陈代谢，并增加肥胖对代谢重要的器官（例如肝脏）造成的损害。通过研究这些变化是如何发生的以及它们对十二指肠的作用，我们希望了解它们如何加剧与肥胖相关的健康问题，并确定药物治疗这些疾病的新靶标。为了实现这一目标，我们将：创建一张详细的地图，了解瘦（非肥胖）和肥胖个体的十二指肠的差异。我们将研究不同类型的细胞及其活性，以及​​生活在十二指肠中的细菌。通过比较瘦和肥胖的人，我们将确定肥胖如何影响十二指肠并找到有助于代谢问题的重要途径。然后，我们将使用此信息来研究这些变化如何影响十二指肠的功能。为此，我们将使用实验室中的人类细胞来种植少量的十二指肠模型。这些类器官将有助于我们了解十二指肠的变化如何影响肠道阻止有害物质的能力，细胞如何更新自身以及这些变化如何导致代谢问题。然后，我们将测试相同的机制是否会像肥胖一样恶化小鼠的新陈代谢。最后，我们将探讨改善肥胖症中十二指肠的健康是否可以帮助减少肥胖对代谢的负面影响。使用类器官，我们将测试不同的治疗方法，以找到最有效的方法。然后，我们将向发展肥胖症的小鼠提供这种治疗方法，看看它是否改善了它们的新陈代谢，包括它们如何处理糖和组织中的损害和炎症水平。这项工作将发现，这项工作将发现十二指肠如何受肥胖的影响，确定这些变化是否会导致进一步的健康问题，并确定这些变化是否会导致这些变化或防止新代谢性疾病的人。