Mathis, Diane J., PhD
Making, breaking and remaking immunological tolerance
General Research Subject: Type 1 Diabetes
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2012
Project End Date: June 30, 2016
In broad terms, the lab studies how individuals maintain immunological tolerance to self-constituents. We focus on mouse models of type-1 diabetes (T1D) and autoimmune polyglandular syndrome type-1 (APS-1), and translate key findings to human patients where feasible. Fellows will receive training in a large palette of genetic, molecular, biochemical, cellular and whole-animal techniques. Major mechanistic questions they can choose to address include: What molecular processes are involved in the control of immunological tolerance by the transcriptional regulator, AIRE, the protein mutated in APS-1 patients? How does the gut microbiota protect from development of T1D by genetically prone individuals? How do regulatory T cells rein in the pro-diabetic activities of natural killer cells, a new-found player in T1D?
Mentor: Diane J. Mathis, PhD Postdoctoral Fellow: Kushagra Bansal, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Type 1 diabetes is a chronic autoimmune disorder associated with selective destruction of insulin-producing pancreatic beta cells by self-reactive immune cells and pancreatic islet inflammation. The key to this disorder is a genetic or acquired defect in immunological tolerance, a network of central and peripheral mechanisms that guards against abrupt immune responses towards self-antigens. Central tolerance is enforced by medullary thymic epithelial cells (MECs) which transcribe thousands of genes coding for peripheral tissue antigens (PTAs) under the transcriptional control of the autoimmune regulator Aire, and T cells reactive to these antigens are deleted ‘‘centrally’’ in the thymus. The major goal of our research is to understand the fundamental mechanisms involved in control of immunological tolerance by Aire. Notably, a substantial fraction of humans with a mutated AIRE gene develop type-1 diabetes at an early age.
Aire exhibits many features reminiscent of classical transcriptional regulators, but several lines of evidence suggest that it does not bind to promoter or enhancer elements directly, suggesting that it might have procured certain unique strategies to drive transcription of a large, but select, portion of the genome specifically in MECs. The aim of the current project is to elucidate molecular mechanisms underlying control of gene expression by Aire using mass spectrometry-based proteomics and other relevant approaches. We believe that our findings will serve as a paradigm to understand pathogenesis of diabetes and other related autoimmune disorders and may assist in design of novel therapeutics.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The continuous incidence and alarmingly raising numbers of patients with diabetes have stressed on the urgency of developing novel diagnostic and therapeutic intervention strategies. Although the current knowledge strongly supports the role of breakdown of tolerance and self-destructive immune cells in development of Type 1 diabetes, the information about molecular mechanisms involved in control of immunological tolerance remains obscure. The purpose of this project is to advance our understanding of the molecular mechanisms involved in expression of self-antigens in thymus, which is key to development of immunological tolerance. The information derived from this project will provide a rational basis for future studies to explore the development of novel therapeutics and help in improvisation of life of diabetic patients or individuals who are at risk of developing diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes is one of the prevalent diseases in society and each individual is related to a diabetic patient directly or indirectly. As a life scientist, I am keen to find new solutions to current scientific problems in the area of immune-pathology and rampant incidence of diabetes is motivation for this project. The diabetes research is one of finest example of close interlock between basic science and clinical translational research. Although, insulin injection is one of the most popular therapies for diabetes, it is not a cure, warranting the better understanding of disease setting and development of advanced therapeutic measures. This award will help us to understand the basic mechanisms associated with development of autoimmune diseases, in particular diabetes, which could be translated in development of novel approaches for treatment of diabetic patients.
In what direction do you see the future of diabetes research going?
The current therapeutical approaches are targeted toward treatment of diabetes by insulin replacement but do not focus on the reason for the need of insulin replacement. These observations strongly recommend three major steps for better cure of diabetes- 1- Advanced diagnostic tools for early detection of disease 2- Improved therapeutic strategies for onset of immunological tolerance 3- Novel approaches for pancreatic beta cell regeneration I believe that the balance between basic research for better knowledge of mechanistic details pertaining to disease onset and translational research for development of novel tools for the treatment and cure of diabetes, will pave a way towards a diabetes-free world.
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