Bradshaw, Elizabeth M., PhD
The T cell derived cytokine, IL-21 in human type 1 diabetes
General Research Subject: Type 1 Diabetes
Focus: Genetics, Genetics\Type 1 Diabetes, Immunology
Type of Grant: Junior Faculty
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Genome-wide association studies, which compared the DNA sequence variation of people with type 1 diabetes to people without the disease, found a number of DNA variants that exist in a higher frequency in the people with the disease compared to the non-diabetic people. Many of the genes that are physically close to these variants, and therefore most likely influenced by them, have been identified. The next step is to determine the mechanism of how these genes influence the etiology, progression, or pathology of diabetes. Variants near the Il21 gene have been identified in these studies, and therefore it could be hypothesized that the diabetes-associated variant somehow effects transcription, which is the first step in converting the information in the gene to protein. The IL-21 protein has potent effect on cells of the immune system. Type 1 diabetes is an autoimmune disease, in which the immune system attacks and destroys the insulin-producing beta cells in the islets of Langerhans.
The hypothesis proposed here is that there is increased production of IL-21 in subjects with type 1 diabetes, which contributes to the pathogenesis of disease. Mouse models examining this gene locus have shown that IL-21 is very important for the disease in mice. The purpose of this proposal is to demonstrate that the genetic variant that is associated with type 1 diabetes results in increased IL-21 protein, and that IL-21 is increased in people with diabetes compared to people without the disease. Therefore, IL-21 may be an excellent target for therapeutic treatments.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The main focus of my research has been examining the role of a subset of immune cells called antigenpresenting cells in the autoimmune disease, type 1 diabetes. Work by myself and others demonstrates that antigen-presenting cells from patients with type 1 diabetes clearly differ from antigen-presenting cells from healthy subjects, and we are focused on determining why that is and what it means for disease progression. Antigen-presenting cells have a great influence over another type of immune cell called T cells, which have been known for a long time to be implicated in the autoimmune component of type 1 diabetes. We are examining how antigen-presenting cells from patients with type 1 diabetes dictate how T cells will behave, such as, which signaling molecules they will secrete and what surface identifying proteins they will express. Better understanding of these cell populations and the molecules they produce will identify potential targets for therapeutic intervention.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The main goal of this proposed research is to demonstrate that the IL-21 protein is a reasonable therapeutic target to explore for type 1 diabetes treatment. Type 1 diabetes is thought to be a T cellmediated autoimmune disease characterized by the destruction of the insulin-producing ß-cells in the islets of Langerhans of the pancreas, and it also has a significant genetic component. In humans, the genetic locus that encodes IL-21 is associated with type 1 diabetes susceptibility. IL-21 is a signaling molecule produced by T cells, which has potent effects on many other cell types, especially other immune cells. We predict that results of this study will support neutralization of IL-21 as a therapeutic target for the immune component of T1D and to halt the autoimmune attack of the ß-cells.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Type 1 diabetes is a chronic disease that affects children and adults, and the incidence is steadily rising. While type 1 diabetes is rarely fatal, it can usually be managed by injected insulin treatment, treatment must be continued indefinitely, and there are still a lot of complications that can arise. A treatment that can stop the autoimmune attack of the ß-cells is still needed. This award will make a large impact in my ability to continue to study type 1 diabetes. Funding of this grant proposal will allow me to pursue a project combining two of my areas of focus, antigenpresenting cells and genotype-phenotype correlations; looking at a pathway that may have an important role in the autoimmune component of type 1 diabetes and hopefully will identify new targets to manipulate therapeutically for the treatment of type 1 diabetes.
In what direction do you see the future of diabetes research going?
There are a number of genetic loci that have been associated with type 1 diabetes, in which the implicated proteins are part of the immune system. The next step is to understand how these Implicated proteins are involved in disease progression. Then, this information will be used for identification of at risk subjects and development of new therapeutics targeting these proteins and the pathways they identify.
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