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

1型糖尿病（T1D）影响英国超过40万人，其中包括多达3万名儿童。治疗包括终身每天注射胰岛素，这种疾病是由于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正常产生胰岛素的细胞。该项目旨在进一步了解1型糖尿病（T1D）的危险因素，特别是是否有可能通过改变环境来降低T1D的风险。自20世纪50年代以来，T1D的发病率逐年上升，与儿童感染更频繁地使用抗生素相吻合。一种理论是抗生素破坏了肠道微生物（称为微生物组）的平衡。已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，与没有T1D的儿童的微生物组相比，微生物的类型，频率和多样性存在许多差异。T1D的小鼠模型，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组的发育以及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，微生物组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。目前正在探索具有功能性或非功能性Dexi基因对微生物组的影响，初步证据表明，缺乏功能性Dexi基因会改变微生物组。此外，还将探索改善微生物组健康的措施对T1D发展的影响。这项工作正在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并行进行。宠物狗和猫可以像人类一样发展为自发性胰岛素依赖型糖尿病，重要的是它们比NOD模型具有优势，因为它们共享我们的环境。了解遗传和环境在宠物糖尿病风险中的作用可能会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，但正在开发一种称为纳米的新方法。在这个项目中，新的纳米抗体将被测试，看看它是否能有效地检测德西。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进一步详细的探索。

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.