The overall goal of this P01 application is to continue address of the hypothesis that antigen presenting cells(dendritic cells, macrophage/monocytes), through their interaction with components of the cellular immunesystem (NK T-cells, regulatory T cells), form a critical facet for the immune dysregulation which results intype 1 diabetes. This P01 renewal will examine this hypothesis with three separate but highly interactiveProjects and will be supported by two well-established Core facilities (A-Administration; B-Pathology &Immunology). The Program requires an effective Administrative Core component as a central element offiscal and scientific coordination. The four goals of Core A are as follows: 1) To coordinate the budgetary andfiscal aspects of the Program. The proposed Program involves direct cost disbursements to investigators ofthe three Projects and two Cores; hence careful oversight represents an absolute administrativerequirement. 2) To facilitate communication among investigators within the Program. This will take formthrough performance of many functions ranging from regularly scheduled meetings between Programinvestigators to training of Project Investigators by Program Cores. 3) To coordinate the goals and activitiesof the PO1 as a Program Executive Committee and respond to input provided by an External AdvisoryCommittee, both for the purpose of maximizing the progress and success of the Program: These committeeswill meet on a regularly scheduled basis and provide counsel to the Program Investigators regarding theirprogram and recommendations for improvement. 4) To organize the collection of human materials, generateappropriate data sets, provide statistical support to the Program, assure compliance with appropriateregulatory bodies and edicts (e.g., IRB, IACUC, Health Insurance Portability and Accountability Act, etc.) andfacilitate communication of Program results. In addition to the aforementioned functions, the administrativestaff of the Program will also be responsible for communication with the NIH staff, for assistance withpublications and presentation of Program results. The successful completion of these P01 studies shouldprove beneficial to improving our understanding of those events critical to the pathogenesis and naturalhistory of type 1 diabetes, identifying markers that enhance our ability to monitor cellular immune activities inthe disease, and developing immunotherapies capable of preventing or reversing the disorder.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-TP-I (S1))
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University of Florida
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Perry, Daniel J; Wasserfall, Clive H; Oram, Richard A et al. (2018) Application of a Genetic Risk Score to Racially Diverse Type 1 Diabetes Populations Demonstrates the Need for Diversity in Risk-Modeling. Sci Rep 8:4529
Chen, Yi-Guang; Mathews, Clayton E; Driver, John P (2018) The Role of NOD Mice in Type 1 Diabetes Research: Lessons from the Past and Recommendations for the Future. Front Endocrinol (Lausanne) 9:51
Kusmartseva, Irina; Beery, Maria; Philips, Tiffany et al. (2018) Hospital time prior to death and pancreas histopathology: implications for future studies. Diabetologia 61:954-958
Hu, Ronghua; Xia, Chang-Qing; Butfiloski, Edward et al. (2018) Effect of high glucose on cytokine production by human peripheral blood immune cells and type I interferon signaling in monocytes: Implications for the role of hyperglycemia in the diabetes inflammatory process and host defense against infection. Clin Immunol 195:139-148
Smith, Mia J; Rihanek, Marynette; Wasserfall, Clive et al. (2018) Loss of B-Cell Anergy in Type 1 Diabetes Is Associated With High-Risk HLA and Non-HLA Disease Susceptibility Alleles. Diabetes 67:697-703
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
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
Posgai, Amanda L; Wasserfall, Clive H; Kwon, Kwang-Chul et al. (2017) Plant-based vaccines for oral delivery of type 1 diabetes-related autoantigens: Evaluating oral tolerance mechanisms and disease prevention in NOD mice. Sci Rep 7:42372
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
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

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