The migration of pathogenic T cells to the pancreas, and their subsequent activation and proliferation, are important steps in the pathogenesis of type I diabetes. CD98 is a heterodimeric transmembrane protein that functions in amino acid transport and integrin signaling. Integrin expression and function are important for autoimmune diabetes in the NOD mouse model, and proliferation of T cells in pancreatic draining lymph nodes is a hallmark of disease. Therefore we have begun investigating CD98 as a potential target in type I diabetes. Our preliminary data shows that T cells in which CD98 has been targeted are unable to transfer disease, while transfer of control T cells causes beta cell destruction and overt diabetes. Our overall hypothesis is that CD98 controls migration or proliferation of diabetogenic T cells, and thus is a potential target for disease intervention. The research proposed in this application will Investigate the cellular and biochemical mechanisms by which CD98 deletion protects from type I diabetes, and to study potential side effects of CD98 targeting on normal immune responses.

Public Health Relevance

Blocking the autoimmune attack mediated by lymphocytes in type I diabetes is a high priority, both to prevent the disease, and to stop its recurrence after islet cell transplant. We found that deleting CD98 on T lymphocyte immune cells makes them unable to cause experimental type I diabetes. We are proposing to investigate the mechanism of this protection, and to test what CD98 targeting might do to normal immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK090416-04
Application #
8594243
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2011-01-15
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2014
Total Cost
$150,979
Indirect Cost
$11,184
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Cantor, Joseph M (2014) CD98 is a potential target for ablating B cell clonal expansion and autoantibody in multiple sclerosis. J Neuroimmunol 274:230-3
Cantor, Joseph M; Ginsberg, Mark H (2012) CD98 at the crossroads of adaptive immunity and cancer. J Cell Sci 125:1373-82
Cantor, Joseph; Slepak, Marina; Ege, Nil et al. (2011) Loss of T cell CD98 H chain specifically ablates T cell clonal expansion and protects from autoimmunity. J Immunol 187:851-60