MRC TS Award: Genes and Environment in Diabetes Mellitus: A multi-species approach
Lead Research Organisation:
Royal Veterinary College
Department Name: Clinical Sciences and Services
Abstract
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.
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.
Technical Summary
Aims: The aim of this project is to further our understanding of the biology of the DEXI gene which has been associated with susceptiblity to multiple autoimmune diseases including type 1 diabetes (T1D), multiple sclerosis and primary biliary cirrhosis. The specific questions of the functional impact of this gene in the context of the immune system and the microbiome will be addressed. Preliminary evidence suggests that Dexi alters the microbiome, resulting in depletion of diabetes-protective metabolites.
Objectives: The objectives of this study are to evaluate the impact of DEXI knockout on diabetes suceptibility, the microbiome and the function of the immune system. Additionally, this project will examine the functionality of a novel nanobody to facilitate study of DEXI protein across species, including humans, since detection of endogenous Dexi with polyclonal antibodies has been very challenging to date.
In parallel, work is also underway to evaluate the client-owned domestic pet dog and cat, which also suffer from spontaneous diabetes, as a potential spontaneous models for study of the microbiome in in diabetes mellitus.
Methodology: Gene knockdown has already been achieved using CRISPR-Cas9 technology in the non-obese diabetic (NOD) model. Phenotyping to dates has included metabolomics, 16srRNA sequencing and single cell RNA-Seq of selected cell types. Microbiome transfer experiments have also been undertaken in the NOD model in the presence and absence of Dexi and will be analysed to determine their success in altering the microbiome and in preventing diabetes.
Scientific and medical opportunities: Discovery of novel pathways in autoimmune disease susceptibility offers new opportunities for therapeutic or preventative intervention.
Objectives: The objectives of this study are to evaluate the impact of DEXI knockout on diabetes suceptibility, the microbiome and the function of the immune system. Additionally, this project will examine the functionality of a novel nanobody to facilitate study of DEXI protein across species, including humans, since detection of endogenous Dexi with polyclonal antibodies has been very challenging to date.
In parallel, work is also underway to evaluate the client-owned domestic pet dog and cat, which also suffer from spontaneous diabetes, as a potential spontaneous models for study of the microbiome in in diabetes mellitus.
Methodology: Gene knockdown has already been achieved using CRISPR-Cas9 technology in the non-obese diabetic (NOD) model. Phenotyping to dates has included metabolomics, 16srRNA sequencing and single cell RNA-Seq of selected cell types. Microbiome transfer experiments have also been undertaken in the NOD model in the presence and absence of Dexi and will be analysed to determine their success in altering the microbiome and in preventing diabetes.
Scientific and medical opportunities: Discovery of novel pathways in autoimmune disease susceptibility offers new opportunities for therapeutic or preventative intervention.
People |
ORCID iD |
| Lucy Jane Davison (Principal Investigator / Fellow) |