Grant: Project Grant

'STING-associated vasculopathy with onset in infancy' (SAVI) is a rare, but increasingly recognized, disease of children. Individuals with this condition have been reported in many countries, including Canada. The condition is due to mutations in a gene known as STING (that stands for STimulator of INterferon Genes), that trigger the constant activation of the STING protein. STING is normally involved in the production of interferons and other inflammatory proteins as a way to deal with infections by viruses and bacteria. Although STING helps protect the host from the effects of viral or bacteria attack, if it is over-active it can lead to excess inflammation. Therefore, the continuous activation of STING due to the activating mutations in SAVI lead to tissue damage. Thus, children with SAVI become ill, develop rashes, severe lung inflammation, and gangrene of fingers and toes, as well as ears and nose. Hand and foot amputations can be required. Thus far, drug treatments have not been completely effective. The gangrene is due to blood vessel damage and blockages that starve tissues for oxygen and nutrients. The vessel damage, known as vasculopathy, accounts for the 'V' in SAVI. To study this condition we developed a mouse model, based on introducing one of the mutant human STING genes (identified in children), into mice via genetic engineering (a.k.a.transgenic technology). Our model is unique in that the mice, much like the children, develop blood vessel damage, leading to paw damage and inflammation as well as damage to other extremities, including ears and tail. With the advanced imaging methods we have, we have been able to see the blood vessel blockages. Our plan is now to define how different cells and other factors (including cold exposure) are responsible for blood vessel damage in our mice. Importantly, we will also evaluate a variety of therapies in using the mice, that are potentially applicable to this devastating disease of children.