MRC TS Award: Genes and Environment in Diabetes Mellitus: A multi-species approach

MRC TS 奖：糖尿病的基因与环境：多物种方法

• 批准号: MR/X023559/1
• 负责人: Lucy Jane Davison
• 金额: $ 50.36万
• 依托单位: Royal Veterinary College
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX023559%2F1
• 关键词: MRC; TS; Award; Genes; Environment

Type 1 diabetes (T1D) affects more than 400,000 people in the UK including up to 30,000 children. Treatment involves lifelong daily insulin injections and the disease arises as the result of genetic and environmental factors, which cause the immune system to destroy the cells in the pancreas which normally produce insulin. This project is aimed at understanding more about the risk factors involved in type 1 diabetes (T1D) and in particular whether it might be possible to reduce the risk of T1D by making environmental changes.The incidence of T1D has been rising year on year since the 1950s, coinciding with more frequent use of antibiotics for childhood infections. One theory is that antibiotics disrupt the balance of micro-organism in the gut (known as the microbiome). The microbiome is known to be involved in the development of the immune system and a healthy microbiome is thought to be involved in protecting against the development of T1D. Studies of the microbiome in children affected with T1D demonstrate many differences in the type, frequency and diversity of micro-organisms compared to the microbiome of children without T1D. Mouse models of T1D such as the NOD (non-obese diabetic) mouse have also demonstrated a relationship between antibiotic use and T1D risk. In addition, recent evidence has suggested that a gene called DEXI may be involved in microbiome development, as well as T1D risk. This proposal will examine the relationship between the microbiome, the DEXI gene and T1D risk. In the NOD model, the microbiome is being examined by looking at the genetic material from micro-organisms in the faeces, throughout the life course. The effect on the microbiome of of having an functional or non-functional Dexi gene is being explored, with preliminary evidence suggesting that the absence of a functioning Dexi gene alters the microbiome. In addition, the impact of measures to improve microbiome health on the development of T1D on this model will also be explored.This work is being done in parallel with a search for new spontaneous diabetes models for studying the microbiome and diabetes development. Pet dogs and cats can develop spontaneous insulin-dependent diabetes mellitus just like humans and importantly they have the advantage over the NOD model that they share our environment. Understanding the role of genetics and environment in diabetes risk in pets may offer important insights and benefits in human diabetes.Finally, the role of DEXI in the human immune system will be explored. At present, it is challenging to detect the Dexi protein, but a new method for doing this, known as a nanody, is being developed. in this project, the new nanobody will be tested to see if it is effective at detecting Dexi. This would allow the relationship between DEXI, the microbiome and the development of the human immune system to be explored in further detail in future.

1 型糖尿病 (T1D) 影响着英国超过 400,000 人，其中包括多达 30,000 名儿童。治疗包括终生每日注射胰岛素，这种疾病是由遗传和环境因素引起的，这些因素导致免疫系统破坏胰腺中通常产生胰岛素的细胞。该项目旨在更多地了解 1 型糖尿病 (T1D) 的危险因素，特别是是否可以通过改变环境来降低 T1D 的风险。 20 世纪 50 年代，恰逢抗生素更频繁地用于治疗儿童感染。一种理论认为抗生素会破坏肠道微生物（称为微生物组）的平衡。众所周知，微生物组参与免疫系统的发育，健康的微生物组被认为参与预防 T1D 的发展。对患有 T1D 的儿童的微生物组的研究表明，与未患 T1D 的儿童相比，微生物组在微生物的类型、频率和多样性方面存在许多差异。 T1D 小鼠模型，例如 NOD（非肥胖糖尿病）小鼠，也证明了抗生素使用与 T1D 风险之间的关系。此外，最近的证据表明，一种名为 DEXI 的基因可能与微生物群的发育以及 T1D 风险有关。该提案将研究微生物组、DEXI 基因和 T1D 风险之间的关系。在 NOD 模型中，通过观察整个生命过程中粪便中微生物的遗传物质来检查微生物组。具有功能性或非功能性 Dexi 基因对微生物组的影响正在被探索，初步证据表明，功能性 Dexi 基因的缺失会改变微生物组。此外，还将探讨改善微生物组健康的措施对该模型上 T1D 发展的影响。这项工作与寻找新的自发性糖尿病模型以研究微生物组和糖尿病发展的同时进行。与人类一样，宠物狗和猫也会患上自发性胰岛素依赖型糖尿病，重要的是，它们比 NOD 模型有一个优势，那就是它们与我们共享环境。了解遗传和环境在宠物糖尿病风险中的作用可能为人类糖尿病提供重要的见解和益处。最后，将探讨 DEXI 在人类免疫系统中的作用。目前，检测 Dexi 蛋白具有挑战性，但一种称为 nanody 的新方法正在开发中。在这个项目中，我们将测试新的纳米抗体是否能有效检测 Dexi。这将使 DEXI、微生物组和人类免疫系统发育之间的关系在未来得到更详细的探索。