Lan, Michael , PhD
INS-VNTR and AIRE regulate differential insulin expression in human thymic epithelial cells
General Research Subject: Type 1 Diabetes
Focus: Genetics\Type 1 Diabetes, Immunology
Type of Grant: Basic Science
Project Start Date: January 1, 2013
Project End Date: December 31, 2015
Diabetes Type: Type 1 diabetes
This proposal is to investigate the molecular mechanism underlying each individual who displays differential autoimmune tolerance to the insulin gene. We discovered that an autoimmune regulator (AIRE) controls the insulin variable number of tandem repeat (INS-VNTR) locus in human thymus, which determines the expression levels of insulin gene. The variable level of insulin expression in thymus is the determining factor for the subsequent insulin autoimmune tolerance induction. Since INS-VNTR contains unique tandem repeat structural feature and specific for the human insulin gene, it is important to dissect the functional components critical for the insulin gene regulation.
Our study is focusing on the molecular mechanisms of AIRE interaction with INS-VNTR to contribute to the insulin autoimmunity in T1D. These studies focus on the interaction of AIRE and INS-VNTR that leads to the normal tolerance induction. The outcomes of this study could provide critical information to understand and seek improvement of autoimmune therapies as well as means of disease prevention.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
Insulin autoimmunity has been closely associated with the development of type 1 diabetes (T1D). However, it is unclear why the self insulin peptide escapes immune tolerance and causes the autoimmune destruction of pancreatic beta cells. Studies focused on the molecular mechanisms leading to the induction of normal tolerance would provide critical information about the disease process and could lead to the improvement of disease prevention and therapies for this autoimmune form of diabetes. The insulin minisatellite, variable number of tandem repeat (INS-VNTR/IDDM2) locus, is closely associated with T1D. INS-VNTR is associated with the regulation of constitutive insulin expression in both the thymus and pancreas.
Our studies show that the AIRE protein positively regulates the INS-VNTR region in a haplotype-specific manner in thymic epithelial cells. These data have led us to hypothesize that AIRE in the thymus can modulate the unique INS-VNTR to control insulin gene expression. The levels of insulin expression in the thymus likely induce either insulin tolerance or autoimmunity related to the development of T1D. This study is novel because of the unique structural feature (multiple tandem repeats) of INS-VNTR target. We will analyze the VNTR tandem repeat components and the functional domains of the AIRE protein to determine how that interaction modulates insulin expression in the thymus.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Understand the mechanism of insulin autoimmune tolerance induction is critical for prevention and treatment of T1D. Insulin autoimmune tolerance is body's immune system recognizes insulin as self protein and generates tolerance by not attacking its presence. Our project is designed to understand how the genetic element of an individual influence insulin gene expression in thymus, which subsequently either induces insulin tolerance or autoimmunity. We identified an autoimmune regulator (AIRE) expressed in human thymus that interacts with allelic variations of the human INS-VNTR susceptibility locus associated with insulin gene expression and diabetes mellitus.
The outcome of our study will provide direct evidence to support that the class III VNTR haplotype is protective and the class I VNTR haplotype is predisposing to T1D. The information will greatly advance our understanding of how to strategize inducing insulin tolerance in contrast to autoimmunity to prevent T1D.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
Diabetes is a devastating disease that affects millions of people. It is dreadful to see your friends, relatives, and other human beings suffer from this disease. I chose diabetes research as my research career more than twenty years ago. Although I am a basic science researcher, I truly believe basic science is the foundation for clinical application. Further, understanding the basic mechanisms of diabetes onset could help us design strategies to prevent or overcome diabetes during the disease process. This award will provide immediate funding to the research personnel and supplies to continue this important project.
In what direction do you see the future of diabetes research going?
Basic research has shed light on how an individual develops diabetes. How the immune system recognizes a self-protein as an autoantigen, which leads to the destruction of pancreatic beta cells. The genetic elements are variable from individuals. What are the mechanisms underlying their genetic background that contributes to the development of diabetes? The information is important for the prediction and prevention of diabetes.
For the treatment of diabetes, regenerative medicine holds great promise of generating clinically useful islets by self islet replication, the reprogramming of other cell types, and islet cell neogenesis. The basic sciences also contribute greatly to the understanding of how to manipulate islet cell growth and differentiation for clinical application.
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