Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by selective destruction of insulin secreting beta-cells found in pancreatic islets of Langerhans. Viral infection is one event proposed to initiate beta-cell damage during the development of this disease. While recent studies have begun to unravel the mechanisms by which virus infection modulates the lymphocytic response, few studies have examined the impact of virus infection on macrophage activation or the direct effects of virus infection on beta-cell function and viability. The broad goals of this research are to elucidate the biochemical mechanisms by which virus infection regulates macrophage activation and to determine the virus-activated pathways that contribute to the loss of beta-cell function and viability. Using a virus known to induce diabetes in susceptible mice, we have recently identified three novel antiviral signaling pathways that regulate inflammatory gene expression in macrophages. In response to a virus infection, the fate of beta-cells appears to be dependent on the response elicited, where an inflammatory response appears to result in beta-cell necrosis, and in the absence of inflammation beta-cell apoptosis ensues. There are two specific aims: 1. To test the hypothesis that the activation state of PI3K determines the response of macrophages to virus infection. When PI3K is in an activated state, virus infection stimulates the expression of inflammatory genes such as IL-1, iNOS and COX-2. When inhibited, virus infection induces macrophage apoptosis. 2. To elucidate the pathways responsible for regulating the response of beta-cells to a virus infection. Specific experiments will determine the mechanisms by which virus infection stimulates inflammatory gene expression by beta-cells, and the pathways and determinants that are responsible for beta-cell death, either by necrosis or apoptosis. A number of biochemical, molecular, immunological, histochemical, and transgenic techniques will be utilized to investigate the cellular pathways through which viral infection stimulates macrophage activation and modulates beta-cell function and viability. It is hoped that insights into regulation of macrophage and beta-cell responses to virus infection gained from these proposed studies will influence the design of therapeutic strategies aimed at the prevention of this debilitating disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Bourcier, Katarzyna
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Medical College of Wisconsin
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Khan, Parvez; Idrees, Danish; Moxley, Michael A et al. (2014) Luminol-based chemiluminescent signals: clinical and non-clinical application and future uses. Appl Biochem Biotechnol 173:333-55
Oleson, Bryndon J; Broniowska, Katarzyna A; Schreiber, Katherine H et al. (2014) Nitric oxide induces ataxia telangiectasia mutated (ATM) protein-dependent ?H2AX protein formation in pancreatic ? cells. J Biol Chem 289:11454-64
Freudenburg, Wieke; Gautam, Madhav; Chakraborty, Pradipta et al. (2013) Reduction in ATP levels triggers immunoproteasome activation by the 11S (PA28) regulator during early antiviral response mediated by IFNýý in mouse pancreatic ýý-cells. PLoS One 8:e52408
Broniowska, Katarzyna A; Diers, Anne R; Corbett, John A et al. (2013) Effect of nitric oxide on naphthoquinone toxicity in endothelial cells: role of bioenergetic dysfunction and poly (ADP-ribose) polymerase activation. Biochemistry 52:4364-72
Meares, Gordon P; Fontanilla, Dominique; Broniowska, Katarzyna A et al. (2013) Differential responses of pancreatic ýý-cells to ROS and RNS. Am J Physiol Endocrinol Metab 304:E614-22
Freudenburg, Wieke; Gautam, Madhav; Chakraborty, Pradipta et al. (2013) Immunoproteasome Activation During Early Antiviral Response in Mouse Pancreatic *-cells: New Insights into Auto-antigen Generation in Type I Diabetes? J Clin Cell Immunol 4:
Baldwin, Aaron C; Green, Christopher D; Olson, L Karl et al. (2012) A role for aberrant protein palmitoylation in FFA-induced ER stress and ?-cell death. Am J Physiol Endocrinol Metab 302:E1390-8
Mboko, Wadzanai P; Mounce, Bryan C; Wood, Brittani M et al. (2012) Coordinate regulation of DNA damage and type I interferon responses imposes an antiviral state that attenuates mouse gammaherpesvirus type 68 replication in primary macrophages. J Virol 86:6899-912
Andreone, Teresa; Meares, Gordon P; Hughes, Katherine J et al. (2012) Cytokine-mediated *-cell damage in PARP-1-deficient islets. Am J Physiol Endocrinol Metab 303:E172-9
Christmann, Benjamin S; Moran, Jason M; McGraw, Jennifer A et al. (2011) Ccr5 regulates inflammatory gene expression in response to encephalomyocarditis virus infection. Am J Pathol 179:2941-51

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