Interdisciplinary Initiatives Program Round 11 - 2022
Calvin Kuo, Medicine (Hematology)
Jin Billy Li, Genetics
Inflammatory bowel diseases (IBD) are characterized by persistent, relapsing inflammation of the gastro-intestinal tract. However, little is known about the initial triggers of this inflammation, delaying the development of new therapies and the usage of treatments for other diseases that may work for IBD. However, we have identified a new type of genetic risk variants enriched in patients with IBD and other immune system-related diseases that inhibit the ability of the protein ADAR1 to edit doublestranded RNAs (dsRNAs) from genes near the variants. Without editing by ADAR1, these dsRNAs are presumed to be recognized by the cell as a viral infection leading to inflammation. To interrogate this possibility, we will first measure Adar1’s activity in intestine of mice modified to carry a controllable form of Adar1. This work will identify how Adar1 activity affects the health of the intestine. Additionally, we will examine the DNA of adult IBD patients for these genetic risk variants and compare their variant burdens to the severity of their disease and expression levels of inflammationassociated genes in tissue sample from their intestines. This investigation will identify how these risk variants affect the severity of IBD. The studies in this project will lead to a paradigm shift in the understanding and treatment of IBD and serve as a foundation for future investigations in identifying new and repurposed therapeutics for IBD, as well as clarifying the roles played by ADAR1 and RNA editing in preventing IBD and other immune-mediated diseases.