The role of nucleic acid sensing in triggering autoimmune diabetes
- Research Opportunity
- PhD, Masters by Research, Honours, Master of Biomedical Science
- Project Status
- Medicine and Radiology
- St Vincent's Hospital
|A/Prof Helen Thomas||Personal web page|
|Dr Tom Brodnicki||Personal web page|
Important fundamental questions about the early triggering events in development of autoimmune diseases such as T1D remain unresolved. Type I interferons (IFN) are downstream of suggested triggers like viruses and an enhanced IFN-regulated gene expression signature has been reported to precede the development of autoimmunity in children at risk of developing T1D, suggesting that type I IFN plays an important role in the initiating event.
Local type I IFN production can also be induced by endogenous signals such as cytosolic DNA. Granzyme A is a protease implicated in the degradation of cytosolic DNA through its ability to activate nucleases of the endoplasmic reticulum-associated SET complex. Recently, we have produced mice lacking granzyme A and discovered that absence of granzyme A accelerates diabetes, and this acceleration is associated with increased cytosolic DNA in immune cells and dependent on an elevated type I IFN signature in islets.
We propose that poor clearance of host nucleic acids, generated without an exogenous infection, may be a trigger for T1D. In particular, we propose a role for the stimulator of interferon genes (STING), a central hub in DNA sensing, which becomes activated and induces interferon production. We have generated mice deficient in granzyme A and STING using CRISPR/Cas9 technology. We will test whether spontaneous autoimmune diabetes, or the accelerated diabetes caused by deficiency of granzyme A, is altered in the absence of STING. These experiments will shed light on the early events in type 1 diabetes pathogenesis, and may point to pathways that can be inhibited in prevention of disease.
This project is conducted in St Vincent’s Institute of Medical Research, Islet Biology Unit.
School Research Themes
PhD, Masters by Research, Honours, Master of Biomedical Science Graduate Research Students who are interested in joining this project will need to consider their elegibility as well as other Graduate Research requirements before contacting the supervisor of this research
For further information about this research, please contact a supervisor.