Grant: Fellowship - PA: Takeda Canada and CIHR Institute of Genetics Rare Diseases

The immune system is a complex reaction that is essential to fight microbes but also prevent development of cancer. A fine-tuned and coordinated regulation of the various actors of the immune system is necessary to mount an effective immune response. Dysregulation of this system leads to unwanted reactions that are harmful for the body. Mutations in key proteins in the immune system can lead to primary immunodeficiencies with the patients unable to fight against pathogens. To design highly specific drugs with high efficacy to treat immune-related diseases, we must understand the mechanisms underlying the fine regulation of the immune system at the levels of protein biochemistry. The STAT1 protein is central to the many aspects of the immune reaction and its mutation or dysregulation causes life threatening conditions, primary immunodeficiency, autoimmunity or cancer. Our understanding of the detailed mechanisms that control the activity of the STAT1 protein remain elusive hampering the design of drugs with high specificity. Proteins are highly regulated by multiple modification that occur on their amino acids. An emerging concept is the regulation by oxidative modifications that occur on Cysteines. These modifications modify the structure and function of proteins making them an interesting target for drug development. In this proposal, I will generate new knowledge of the regulation of STAT1 by oxidative mechanisms with the hope that these finding will unveil specific features that can be used to inspire future drug design.