Immunoproteasome in pancreatic beta cells
General Research Subject: Type 1 Diabetes
Focus: Immunology, Signal Transduction (Non-Insulin Action)\Cytokines and Apoptosis
Type of Grant: Basic Science
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
Type 1 diabetes is an autoimmune disease that results from selective destruction of insulin-producing pancreatic beta-cells. It is one of the most prevalent chronic diseases in the United States and a leading cause of death. Environmental factors, including virus infection, are acknowledged risk factors in type I diabetes, but little is known about the early events in initiation of this disease. We hypothesize that one potential trigger for initiation or potentiation of this disease is a change in the pattern of cytotoxic T-cell ligands generated from beta-cell proteins during antiviral response, and that this change stimulates the expansion of native T cells that cause beta-cells destruction. This hypothesis stems from our recent observation that beta-cells exposed to antiviral interferons accumulate immunoproteasome, the proteolytic complex that specializes in the production of CTL precursors. To test this hypothesis, we developed an approach that allows the identification of large pools of proteasomal product peptides generated from natural cellular substrates. We propose to use this approach to determine the pools of peptides produced in uninfected beta-cells, and in beta-cell exposed to interferons. This work will define whether a change in the pattern of peptides derived from beta-cell proteins is a factor during viral infection of beta-cells and, in the long term, may explain the mechanism by which viral infections initiate or potentiate type I diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
T1D results from autoimmune destruction of insulin producing pancreatic β-cells. Virus infection is an acknowledged risk factor in T1D, but it is unknown how the fundamentally defensive antiviral response turns into autoimmune disease. A possible new insight into this problem is suggested by our recent finding that not only IFN , but also type I IFNs stimulate pancreatic β-cells to express immune proteasome, the protease that produces immunogenic peptides. Especially interesting is the effect of IFN , which is secreted directly by infected cells and prepares neighboring cells to resist viral infection. In other words, the effect of IFN is early, local and does not involve other cell types. We hypothesize that the early induction of immune proteasome in pancreatic β-cells changes the pattern of immunogenic 'self' peptides generated from β-cell proteins and that this change stimulates the expansion of native T cells that cause β-cells destruction. We propose a plan to test this hypothesis and expect that this work will stimulate new directions in T1D research. If our data support a potential involvement of β-cell peptides in an autoimmune response, future tests will define whether abnormal generation and/or presentation of specific peptides triggers an autoimmune response in mice and/or characterizes individuals with T1D; and whether preventing generation and/or presentation of these antigens inhibits autoimmune response. If the immune proteasome has antigen unrelated role, the identified peptides will implicate specific regulatory proteins that need to be removed to accomplish this role. In either case, this study will provide the foundation for a long-term research project addressing the role of immune proteasome in early antiviral responses of pancreatic β-cells, which is yet unknown.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
This project (1) may explain how viral infections predispose certain individuals to T1D, and (2) may suggest new strategies in the prevention and/or treatment of (at least a subset of) T1D patients.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My interest in diabetes research stems from the realization that
our advanced expertise in proteasomal proteolysis may help to
understand T1D development and may suggest new strategies in its
prevention and/or treatment; and that the analysis of proteasomal
proteolysis in pancreatic β-cells may uncover new regulatory aspects of
this major proteolytic system. This ADA award has a major value for me,
as it will catalyze a transition in my research interests and efforts
toward a disease-oriented research with likely future applications.
In what direction do you see the future of diabetes research going?
The field of diabetes research would benefit from attracting an advanced basic research, as the field needs to first understand the molecular mechanisms involved in diabetes development. The role of proteasomal proteolysis in β-cell pathology is a good example of a new direction in diabetes research that is likely to shed light on a key aspect of T1D development and yet has been not investigated in the past years.
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