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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Baldwin, Aaron C; Naatz, Aaron; Bohnsack, Richard N et al. (2018) Cation-Independent Mannose 6-Phosphate Receptor Deficiency Enhances ?-Cell Susceptibility to Palmitate. Mol Cell Biol 38:
Kropp, Erin M; Broniowska, Katarzyna A; Waas, Matthew et al. (2017) Cardiomyocyte Differentiation Promotes Cell Survival During Nicotinamide Phosphoribosyltransferase Inhibition Through Increased Maintenance of Cellular Energy Stores. Stem Cells Transl Med 6:1191-1201
Schwab, Andrew J; Sison, Samantha L; Meade, Michael R et al. (2017) Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons. Stem Cell Reports 9:1839-1852
Oleson, Bryndon J; Broniowska, Katarzyna A; Naatz, Aaron et al. (2016) Nitric Oxide Suppresses ?-Cell Apoptosis by Inhibiting the DNA Damage Response. Mol Cell Biol 36:2067-77
Shaheen, Zachary R; Corbett, John A (2015) Macrophage Expression of Inflammatory Genes in Response to EMCV Infection. Biomolecules 5:1938-54
Broniowska, Katarzyna A; Mathews, Clayton E; Corbett, John A (2015) Reply to Gurgul-Convey and Lenzen: Cytokines, nitric oxide, and ?-cells. J Biol Chem 290:10571
Kulinski, Joseph M; Darrah, Eric J; Broniowska, Katarzyna A et al. (2015) ATM facilitates mouse gammaherpesvirus reactivation from myeloid cells during chronic infection. Virology 483:264-74
Shaheen, Zachary R; Naatz, Aaron; Corbett, John A (2015) CCR5-Dependent Activation of mTORC1 Regulates Translation of Inducible NO Synthase and COX-2 during Encephalomyocarditis Virus Infection. J Immunol 195:4406-14
Kropp, Erin M; Oleson, Bryndon J; Broniowska, Katarzyna A et al. (2015) Inhibition of an NAD? salvage pathway provides efficient and selective toxicity to human pluripotent stem cells. Stem Cells Transl Med 4:483-93
Oleson, Bryndon J; McGraw, Jennifer A; Broniowska, Katarzyna A et al. (2015) Distinct differences in the responses of the human pancreatic ?-cell line EndoC-?H1 and human islets to proinflammatory cytokines. Am J Physiol Regul Integr Comp Physiol 309:R525-34

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