Priya Issuree, PhD, was awarded an R35 Outstanding Investigator Award, a five-year, $1.9 million grant from the National Institute of General Medical Sciences (NIGMS). Issuree’s lab plans to answer a few essential research questions surrounding mutations in autoimmune diseases and their effect on patient outcomes.
Chronic and autoimmune diseases (such as multiple sclerosis, rheumatoid arthritis, and type 1 diabetes) are genetically complex, and being diagnosed with one inextricably impacts a person’s life. It is hard to predict whether and how certain mutations increase disease risk, especially when they are not present in DNA regions that directly code for proteins.
“Recent work has shown that a substantial fraction of non-coding variants linked to autoimmune disease lie in cis regulatory elements (CREs) of T lymphocytes, a subset of immune cells that play vital roles in preserving self-tolerance and preventing autoimmunity,” Issuree said.
The Issuree lab plans to utilize and develop approaches to investigate how specific regions of the genome affect the long-term gene function in T lymphocytes, and to outline how these regions ensure that T cells retain their ability to protect against disease. The goal of the resulting proposal is to understand how CREs modulate programming in genes with long-term functionality during development of the thymus and to define their contribution in chronic diseases.
With a comprehensive set of approaches, the lab will not only establish the foundation for future investigations into mutations associated with autoimmune disorders driven by T cells, but also offer “a conceptual framework and new models for future investigations into disease-related variants that are prevalent in other cell types such as B cells,” another type of immune cells connected to chronic disease.
Results of this research will have lasting influence in the field; particularly because the grant Issuree received is uniquely concept-driven and shifts focus to overall research questions that can spur further study for years to come. This, in turn, will contribute to therapeutic approaches designed to improve the quality of life of patients who struggle with conditions that can affect them for their entire lives.
“Once we define the importance of these genomic regions on long-term gene function and unravel how they alter disease, we will be able to develop appropriate therapeutic strategies to reduce poor disease outcomes,” Issuree said.
She is quick to acknowledge that this important work could not be done alone; she is grateful to many partners and colleagues that have made this project possible.
“Dr. Mohsen Karimi is my collaborator on this grant, and he should be deeply acknowledged for being willing to jump into the unknown with me. I am also thankful to the Inflammation Program, in particular, Dr. Bill Nauseef, who has been my constant advocate. It has been a struggle to do the foundational work to show why studying T cell development is important and he saw the potential right from the start, whereas I had to sweat really hard to convince others,” Issuree said. “Dr. Josalyn Cho, the new program director, was also there for guidance to get this work supported. I would also like to thank the rest of the Inflammation Program for being the strong community every new junior investigator needs.”