Good news in funding appears to come in pairs. The Juvenile Diabetes Research Foundation is supporting the Autoimmune Genetics Laboratory through a Career Development Award. This is a grant that I am particularly happy to receive, not just for the science that will come out of it, but because I have been a long-time admirer of the JDRF, who tirelessly raise money for research on type 1 diabetes. They are not only the leading sponsor of type 1 diabetes research (spending over $1.4 billion on research since 1970), but also take an active role in coordinating researchers and integrating patient into trials to ensure that the best results come from the money spent. As a PhD student with Chris Goodnow, I always joined in the Walk for the Cure fundraiser, and JDRF sponsored my conference travel to the International Immunology Congress in 2004.
Now the JDRF is supporting our research project on the contribution of non-hematopoietic defects to autoimmune diabetes:
The Non-obese diabetic (NOD) mouse is one of the best studied models of common autoimmune disease in humans, with the spontaneous development of autoimmune diabetes. Similar to the way multiple autoimmune diseases run in families of diabetic patients, the NOD mouse strain is also susceptible to multiple autoimmune diseases, with specific disease development depending on slight alterations in the environment and genetics. These results demonstrate the complexity of autoimmune genetics – in both human families and inbred mouse strains there appear to be a subset of genetic loci that skew the immune system towards dysfunction and an additional subset of genetic loci that result in this immune damage affecting a particular target organ. In the case of NOD mice and type 1 diabetic patients these additional genetic factors result in damage to the beta islets of the pancreas. While the previous emphasis on type 1 diabetes was strictly on the immune system, this model suggests the important role the pancreas may play in the disease process. If certain individuals harbour genetic loci that increase the vulnerability of pancreatic islets to immune-mediated damage, the combination of immune and pancreatic loci could provoke a pathology not caused by either set of genes alone.
Current approaches to genetic mapping in both mice and humans are confounded by the large number of small gene associations and are not able to discriminate between these functional subsets of genetic loci. However, we have developed an alternative strategy for functional genetic mapping. Instead of mapping diabetes as the sole end-point, with small genetic contributions by multiple genes, we map discrete functional processes of diabetes development. This has three key advantages. Firstly, as simpler sub-traits there are fewer genes contributing, each with larger effects, making mapping to particular genes more feasible. Secondly, by mapping a functional process within diabetes we start out with functional information for every gene association we find. Thirdly, by mapping a series of functional processes and then building up this genetic information into diabetes as an overall result we gain a more comprehensive view of diabetes, as a network of genetic and environmental influences that cause disease by influencing multiple systems and processes.
In this project we propose to use the functional genetic mapping approach to probe the role of the pancreatic beta islets in the development of diabetes in the NOD mice. We have developed a transgenic model of islet-specific cellular stress which demonstrates that NOD mice have a genetic predisposition of increased vulnerability of the pancreatic islets to dying and hence the development of diabetes. This is a unique model to analyse the genetic, cellular and biochemical pathways that can be altered in the pancreas of diabetes-susceptible individuals, shedding light on the role the beta islets play in the development of disease.