Montana INBRE (IDeA Networks of Biomedical Research Excellence)

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The Montana INBRE Program (IDeA Networks of Biomedical Research Excellence) is a five-year award (2009-2014) by the National Institute of General Medical Sciences (NIGMS) division of the National Institutes of Health (NIH) that builds on the previous successes of the first five-year MT INBRE program (2004-2009) and the three-year BRIN (Biomedical Research Infrastructure Networks) program (2001-2004) awarded to Montana State University. Montana INBRE continues to focus on increasing the biomedical research capacity of Montana by building research infrastructure, supporting faculty and student research, and fostering a state-wide collaborative network. The pathogenesis of infectious disease and health issues related to the environment are two of Montana INBRE’s research foci, areas in which the state is strategically positioned to excel. In addition, MT INBRE is expanding its research into the field of health disparities, an area of great relevance to the state. INBRE positions Montana as a leader in biomedical research and significantly increases education, research, and, ultimately, employment opportunities in the state.

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Author: search.filters.author.Cho, Yangraesearch.filters.applied.f.department: search.filters.department.Animal & Range Sciences.

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    TmpL, a transmembrane protein required for intracellular redox homeostasis and virulence in a plant and an animal fungal pathogen
    (2009-11) Kim, Kwang-Hyung; Willger, Sven D.; Park, Sang-Wook; Puttikamonkul, Srisombat; Grahl, Nora; Cho, Yangrae; Mukhopadhyay, Biswarup; Cramer, Robert A.; Lawrence, Christopher B.
    The regulation of intracellular levels of reactive oxygen species (ROS) is critical for developmental differentiation and virulence of many pathogenic fungi. In this report we demonstrate that a novel transmembrane protein, TmpL, is necessary for regulation of intracellular ROS levels and tolerance to external ROS, and is required for infection of plants by the necrotroph Alternaria brassicicola and for infection of mammals by the human pathogen Aspergillus fumigatus. In both fungi, tmpL encodes a predicted hybrid membrane protein containing an AMP-binding domain, six putative transmembrane domains, and an experimentally-validated FAD/NAD(P)-binding domain. Localization and gene expression analyses in A. brassicicola indicated that TmpL is associated with the Woronin body, a specialized peroxisome, and strongly expressed during conidiation and initial invasive growth in planta. A. brassicicola and A. fumigatus DtmpL strains exhibited abnormal conidiogenesis, accelerated aging, enhanced oxidative burst during conidiation, and hypersensitivity to oxidative stress when compared to wild-type or reconstituted strains. Moreover, A. brassicicola DtmpL strains, although capable of initial penetration, exhibited dramatically reduced invasive growth on Brassicas and Arabidopsis. Similarly, an A. fumigatus DtmpL mutant was dramatically less virulent than the wild-type and reconstituted strains in a murine model of invasive aspergillosis. Constitutive expression of the A. brassicicola yap1 ortholog in an A. brassicicola DtmpL strain resulted in high expression levels of genes associated with oxidative stress tolerance. Overexpression of yap1 in the DtmpL background complemented the majority of observed developmental phenotypic changes and partially restored virulence on plants. Yap1-GFP fusion strains utilizing the native yap1 promoter exhibited constitutive nuclear localization in the A. brassicicola DtmpL background. Collectively, we have discovered a novel protein involved in the virulence of both plant and animal fungal pathogens. Our results strongly suggest that dysregulation of oxidative stress homeostasis in the absence of TmpL is the underpinning cause of the developmental and virulence defects observed in these studies.
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