Mordes, John Peter
Towards new therapeutic approaches to type 1 diabetes based on rat immunobiology
General Research Subject: Type 1 Diabetes
Focus: Genetics\Type 1 Diabetes, Immunology
Type of Grant: Basic Science
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
With previous ADA funding, one member of the T-cell receptor (TCR) 'beta chain family' of genes, Vbeta13a, was found to be a powerful predictor of susceptibility to T1D in rats, and an antibody against Vbeta13 prevents diabetes. The core hypotheses of this follow-up proposal is that recognition of autoantigen by Vbeta13 is the primary event that initiates autoimmune diabetes.
Vbeta13a will be used to study both the cellular and molecular mechanisms of T1D in several rat strains that progress to diabetes via different pathways (as may be the case for children). Aim 1 will analyze the cellular process by which Vbeta13+ T cells cause T1D. It will determine if these cells can cause both 'spontaneous' T1D and virus-triggered T1D; indicate if different therapies may be necessary for different cases of human T1D; and determine if Vbeta13+ T cell expansion is a biomarker of T1D. RNA interference will be tested as a method for preventing diabetes. Aim 2 will create tools (T cell clones and hybridomas) for determining the molecular structure of Vbeta13a and begin to analyze candidate human T1D autoantigens.
Rationale/Relevance: Only recently have TCR genes been found to be important in both mouse and rat T1D. Their importance in human T1D remains an open question. The discovery that an anti-Vbeta13 antibody prevents T1D suggests that it is time to take a fresh look at this concept. These rat studies should reveal much about a fundamental structural component of T1D and lead to translational research.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project is focused on new therapeutic approaches to preventing type 1 diabetes (T1D). For 15 years we have been mapping genes that make rats susceptible to T1D. We found one gene that has a very powerful effect, clearly distinguishing animals susceptible to T1D from animals that are not. It is a member of a large family of genes called T cell receptor beta chain genes. T cells are well know to mediate T1Ds, and the genes that encode T cell receptors on the surface of T cells have long been suspected of playing a role in determining susceptibility, but our models are the first to provide evidence that specific variants may be very important.
With previous ADA funding we discovered this gene, called Tcrb-V13S1A1, and found that cells that express its protein product, called Vbeta13a, are involved early in the process that destroys beta cell. More importantly, we found that eliminating cells with Vbeta13a on their surface is a highly effective way to prevent diabetes.
We believe that recognition of autoantigen by Vbeta13 is the event that initiates juvenile diabetes. We will use Vbeta13a to study mechanisms of T1D in several rat strains. We will determine if these cells cause both spontaneous T1D and virus-triggered T1D, if different therapies may be necessary for different variants of T1D, and if Vbeta13+ can be a biomarker of T1D. RNA interference to block Vbeta 13 will be tested for diabetes prevention. We will also create tools for determining the molecular structure of Vbeta13a and begin to analyze candidate human T1D autoantigens.
Our intention is to use these studies to open up new pathways for treating children at risk for T1D. We will try to learn from the study of Vbeta13 how the disease starts and thus how treatments proposed for children might or might not work. We hope to use these rat studies as a steppingstone in the future to re-analyses of human genetic data to determine if there are Vbeta13 equivalents that have been overlooked or underappreciated.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
A positive outcome of these animal studies will reveal much about a very
fundamental, structural component of this T-cell mediated 'autoimmune'
form of diabetes. That information in turn can be used to help develop
new tests to identify children at risk for diabetes. The majority of
children with juvenile diabetes have no relatives with diabetes, and
understanding this new predisposing genetic element may help in the
design of screening methods.
In addition, the additional understanding we gain should help to design therapies to prevent the disease. The linking of T cell biology with gene sequences could conceivably lead to accurate personal assessments of T1D risk and specific, personalized treatments to prevent it.
Finally, the animal models we have not only make it simpler to detect and identify predisposing genes, but they also provide important platforms in which safely to test new therapies for preventing or reversing juvenile diabetes.
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 cared for patients with diabetes for nearly 30 years and have
seen all of the consequences of this disorder. There is no more
important goal than preventing it.
This award represents the culmination of a 15 year long research effort to find the Tcrb-V13 gene. In close collaboration with my colleagues, a meticulous program of genotyping and animal breeding has brought us to the identify this one, totally unexpected gene.
Understanding how Tcrb-V13S1A1 leads to diabetes would represent the fulfillment of a every physician/scientist's dream of contributing to a successful effort to create new therapeutic modalities for a devastating disease. Work on Vbeta13 may redirect and enhance our understanding of exactly how exactly how juvenile diabetes starts and thereby how to prevent it.
In what direction do you see the future of diabetes research going?
For type 1 or juvenile diabetes, the advent of genome wide scanning
together with the development of biomarkers of inflammation have
revolutionized our understanding of how the disease is initiated, how it
progresses, and how it might be stopped or reversed. The number of
genes associated with the disease has increased ten-fold or more in only
a few years, and biomarker technology is just in its infancy. As
substantial and rapid as these advances have been, however, it is clear
that much more difficult and complicated work needs to be done. 'Next
generation' sequencing technology will bring us an ever more refined
understanding of individual genomes, and that in turn will begin to tell
us finally why one person becomes diabetic and another does not, how to
identify those that will get the disease, and how to prevent it before
The promise of new personalized immunotherapeutics for juvenile diabetes is very bright--as is the promise of beta cell replacement therapy for those who are already ill.
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