While genetic susceptibility and environment clearly represent realms of influence for the development of type 1 diabetes, a series of immunological abnormalities are inherent to the immune dysregulation that results in the autoimmune destruction of pancreatic (3 cells. Indeed, our previous PO1 studies of individuals with or at increased-risk for type 1 diabetes, as well as in the non-obese diabetic (NOD) mouse model of the disease, associated a series of specialized immune system cells and specific mediators with the disorder. However, issues related to the interplay between these specialized cells and the mediators that allow for abnormal immune regulation, the specificity of these immunological defects in type 1 diabetes versus other autoimmune and metabolic disorders, as well as the ontogeny of immune dysregulation in the natural history of the disease (both prior to and after onset) remain unclear. Our goal in seeking renewal of this P01 grant is to address these outstanding issues;all for the continued purpose of testing our hypothesis that antigen presenting cells (dendritic cells, macrophage/monocytes), through their interaction with components of the cellular immune system (iNKT cells, regulatory T cells), form a critical facet to the immune dysregulation which results in type 1 diabetes. This P01 renewal will examine this hypothesis through three separate but highly interactive Projects. The Projects utilize the NOD mouse model and an extremely valuable population of human subjects with or at increased-risk for type 1 diabetes, as well as healthy controls or persons with type 2 diabetes. The PO1 application is comprised of three Projects: Project 1 (S.B. Wilson, PI) - iNKT Cell Gene Expression and Effector Function in Type 1 Diabetes;Project 2 (M. Clare-Salzler, PI) - Interferons alpha/beta in Type 1 Diabetes Pathogenesis;and Project 3 (M. Atkinson, PI) - Immune Regulation and Type 1 Diabetes Pathogenesis. The projects will be supported by two well established Core facilities: A-Administration;B-Pathology &Immunology. The successful completion of these P01 studies should prove beneficial to improving our understanding of those events critical to the natural history of type 1 diabetes, identifying markers that enhance our ability to monitor cellular immune activities in the disease, uncovering the interplay between the genetics, environment and the immune response in the pathogenesis of type 1 diabetes, as well as developing immunotherapies capable of preventing or reversing the disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI042288-14
Application #
8131066
Study Section
Special Emphasis Panel (ZAI1-TP-I (S1))
Program Officer
Bourcier, Katarzyna
Project Start
1997-09-30
Project End
2013-04-30
Budget Start
2011-09-01
Budget End
2013-04-30
Support Year
14
Fiscal Year
2011
Total Cost
$1,117,395
Indirect Cost
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Chen, Jing; Chernatynskaya, Anna V; Li, Jian-Wei et al. (2017) T cells display mitochondria hyperpolarization in human type 1 diabetes. Sci Rep 7:10835
Sebastiani, Guido; Ventriglia, Giuliana; Stabilini, Angela et al. (2017) Regulatory T-cells from pancreatic lymphnodes of patients with type-1 diabetes express increased levels of microRNA miR-125a-5p that limits CCR2 expression. Sci Rep 7:6897
Ratiu, Jeremy J; Racine, Jeremy J; Hasham, Muneer G et al. (2017) Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes. J Immunol 198:4255-4267
Wang, Qiming; Racine, Jeremy J; Ratiu, Jeremy J et al. (2017) Transient BAFF Blockade Inhibits Type 1 Diabetes Development in Nonobese Diabetic Mice by Enriching Immunoregulatory B Lymphocytes Sensitive to Deletion by Anti-CD20 Cotherapy. J Immunol 199:3757-3770
Jackson, Jessica; Posgai, Amanda; Campbell-Thompson, Martha et al. (2017) Insulitis in Autoantibody-Positive Pancreatic Donor With History of Gestational Diabetes Mellitus. Diabetes Care 40:723-725
Newman, Jeremy R B; Conesa, Ana; Mika, Matthew et al. (2017) Disease-specific biases in alternative splicing and tissue-specific dysregulation revealed by multitissue profiling of lymphocyte gene expression in type 1 diabetes. Genome Res 27:1807-1815
Whitener, Robert L; Gallo Knight, Lisa; Li, Jianwei et al. (2017) The Type 1 Diabetes-Resistance Locus Idd22 Controls Trafficking of Autoreactive CTLs into the Pancreatic Islets of NOD Mice. J Immunol 199:3991-4000
O'Kell, Allison L; Wasserfall, Clive; Catchpole, Brian et al. (2017) Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked? Diabetes 66:1443-1452
Newby, Brittney N; Brusko, Todd M; Zou, Baiming et al. (2017) Type 1 Interferons Potentiate Human CD8+ T-Cell Cytotoxicity Through a STAT4- and Granzyme B-Dependent Pathway. Diabetes 66:3061-3071
Delitto, Daniel; Delitto, Andrea E; DiVita, Bayli B et al. (2017) Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response to Promote a Tumor-Tolerant Immune Microenvironment. Cancer Res 77:672-683

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