Interpreting the genetics of type 1 diabetes
Recent technological advances have facilitated genetic association studies on a very large scale, termed genome-wide association studies or GWAS, for many diseases including type 1 diabetes (T1D). As a result, more than 50 regions of the genome are now known to associate with T1D. While this new wealth of information is invaluable, we still know little of the actual function of the many genes implicated in disease.
Dr. Stephan Kissler seeks to understand how the gene variants uncovered by GWAS contribute to disease risk. Investigations in his laboratory focus on the cellular function of T1D genes to unravel how gene variations may impact the immune system, and thereby modulate the risk of autoimmunity. Ultimately, Dr. Kissler and his team hope to uncover key defects in immune regulation that could be targeted for the treatment or the cure of type 1 diabetes.
Lentiviral RNAi, a unique approach to studying T1D genes
During his postdoctoral work at MIT, Dr. Kissler gathered expertise in a new technology that allows his laboratory to easily modulate gene expression in a mouse model of T1D. Using RNA interference, a method to silence gene expression, in combination with lentiviral transgenesis, a method to genetically modify animals, the Kissler laboratory generates mice in which T1D genes identified in patients are targeted. This genetic manipulation is performed in the most widely-used model for T1D, the nonobese diabetic (NOD) mouse, which had long been notoriously difficult to modify genetically. With this new approach, the Kissler laboratory is probing the function of T1D genes in the context of disease, providing new insights into their role in autoimmunity.
Genetic commonalities between T1D and other autoimmune disorders
The vast knowledge relating to autoimmune disease genetics recently gained by GWAS has uncovered a very significant overlap between multiple autoimmune disorders. Of the 56 genomic regions associated with T1D, more than 30 associate with at least one other disease, two thirds of which associate with multiple diseases in addition to T1D. Consequently, knowledge gained from studying genes with multiple associations may be highly relevant to our understanding of more general principles of autoimmunity. In turn, studying these diabetes genes in other disease models (e.g. models for multiple sclerosis, rheumatoid arthritis or Crohn’s disease) may provide additional insight as to their function in T1D. Therefore, Dr. Kissler and his laboratory focus on those diabetes genes that are the most widely associated with additional immune-mediated diseases.
Translation into clinical relevance
Studying gene function in a mouse model of T1D is indispensable, because many insightful experiments cannot be performed in humans for practical and ethical reasons. However, it is also critical that data from mouse studies be replicated with human samples. Dr. Kissler’s laboratory strives to ensure relevance to human T1D by complementing animal experimentation with studies of human cells. Ultimately, Dr. Kissler’s goal is to translate the most promising findings into clinically useful applications, in aspiration of developing preventive or curative treatments for T1D.