Tse, Hubert Ming, PhD
Synergism of innate immune-derived reactive oxygen species and T cell effector responses in Type 1 diabetes
General Research Subject: Type 1 Diabetes
Focus: Immunology, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Phosphatases-Kinases, Signal Transduction (Non-Insulin Action)\Transgenic Models
Type of Grant: Career Development
Project Start Date: July 1, 2012
Project End Date: June 30, 2017
The autoimmune mediated events that lead to the destruction of islet beta cells are caused by T lymphocytes that recognize beta cells as foreign. This recognition instructs other immune cells to produce very reactive molecules called "free radicals". These molecules have the ability to cause significant damage through oxidative stress, which ultimately leads to beta cell death. Furthermore, islet beta cells are very poor at controlling the effects of oxidative stress, which makes them even more sensitive to free radicals. In addition to beta cell damage, free radicals also have an effect on autoreactive T lymphocytes to enhance beta cell destruction. We have shown that the progression of diabetes in the NOD mouse, the most widely used animal model for type 1 diabetes is prevented when the ability to generate free radicals is lost. NOD mice that are genetically unable to produce free radicals do not develop diabetes.
In this proposal we will further characterize how the absence of free radicals prevents type 1 diabetes by performing comparative analysis experiments with mice that can generate free radicals (develop diabetes) with mice that cannot generate free radicals (resistant to diabetes). With a better understanding of how free radicals can promote type 1 diabetes at the immune level, the generation of novel drugs such as SOD mimics may represent viable therapies for the synthesis of free radicals and the prevention of diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our research in Type 1 diabetes is involved in characterizing the importance of free radicals and pro-inflammatory cytokines as it pertains to T cell autoreactivity. By using unique mouse models that are predisposed to developing Type 1 diabetes, but unable to elicit an inflammatory response, we determined that these mice (NOD.Ncf1m1J) are diabetes resistant. Not only is this inflammatory event necessary for the activation of T cell autoreactivity, but also has an important role in downstream complications associated with elevated blood glucose in Type 1 diabetics. Why and how these mice are resistant to diabetes is the subject of our research proposal and by answering these questions, novel immunotherapies may be generated to be used in translational research studies to prevent Type 1 diabetes.
The information that we will obtain from our project will have a profound role in developing novel immunotherapies for diabetes prevention and a potential cure. Immunotherapies that specifically target innate immune cells (macrophages, neutrophils, and dendritic cells) responsible for generating pro-inflammatory cytokines and free radicals may provide an alternative target to directly inhibit T cell autoreactivity without compromising the entire immune system. The hope down the road is that we can develop drugs that preferentially target and destroy autoreactive T cells, but still enable Type 1 diabetics to lead a normal life free from the fear of contracting life-threatening microbial infections.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
My project will help Type 1 diabetics in the future because it will provide information on the possibility of an alternative immunotherapeutic target to prevent T cell autoreactivity. Currently, the available immunotherapies that exhibit efficacy in preventing Type 1 diabetes have many shortcomings such as global immunosuppression and toxicity. Our understanding of the importance of free radicals and their role in initiating pro-inflammatory cytokine synthesis in Type 1 diabetes is lacking, the data that will obtained from my research proposal will help further define the importance of these noxious effector molecules in not only initiating Type 1 diabetes, but also in pancreatic beta cell destruction. Ultimately, the information garnered will lead to the synthesis of immunotherapies that will specifically dissipate free radical and pro-inflammatory cytokine synthesis such as the metalloporphyrin-based catalytic antioxidants that have demonstrated efficacy in other inflammatory-mediated diseases such as asthma and Lou Gehrig’s disease (amyotrophic lateral sclerosis (ALS)).
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have always felt that service to the community is important in my life and my involvement in biomedical research is one of the greatest services that I can provide. It is important that I am personally involved in diabetes research partly due to the fact that my father-in-law died from complications associated with diabetes more than 8 years ago. His death was untimely and a tragedy to our family especially to my mother-in-law. I decided that with my prior research experience in studying innate immunity, the knowledge that I have attained in inflammatory-mediated diseases could be useful for the diabetes community as well. I believe that by recruiting investigators with varying research backgrounds, they can provide a refreshing perspective on issues that have hampered on progress in finding a cure for Type 1 diabetes.
As a recipient of a prestigious American Diabetes Association Career Development Award, obtaining this award will be instrumental for my continual independence as a principal investigator. This award provides the laboratory with the necessary resources to further expand our research focus and to ultimately help discover a cure for Type 1 diabetes.
In what direction do you see the future of diabetes research going?
I envision in the future that the direction of Type 1 diabetes research will be focused on the development of novel antigen-specific immunotherapies that will preferentially prevent T cell autoimmunity without initiating global immunosuppression. By obtaining more knowledge on the signals that initiate and exacerbate T cell autoimmunity in Type 1 diabetes, we can begin to develop more efficient immunotherapies for the treatment and eventual cure of this disease. In addition to novel therapies, by identifying immunological markers of autoreactive T cells that differ from non-autoreactive T cells, this information will be invaluable for prediction and also to obtaining a cure for Type 1 diabetes. As the incidence of Type 1 and 2 diabetes increases, novel translational research studies from the bench will need to be devised and implemented into bedside therapies before this disease becomes a full blown epidemic.
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