Schaefer Lab

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Left-to-right: Brian Schaefer, Trung Ho, Kate Zeigler, Maria Traver, Mouna Lagraoui, Kariana Rios, Celeste Huaman, Chelsi Beauregard (who is actually in the Broder lab, but we claim her as our own)

Schaefer Lab

schaefer_lab_fig1.jpgThe TCR to NF-κB pathway. Following TCR activation, PKCθ is recruited to the immunological synapse. Activated PKCθ phosphorylates CARMA1, resulting in formation of the CARMA1, BCL10, MALT1 (CBM) complex. The CBM complex transmits activating signals that ultimately result in ubiquitination (U) and degradation of the NF-κB inhibitor, IκBα. NF-κB then translocates to the nucleus and activates transcription of genes required for T cell proliferation and differentiation.schaefer_lab_fig2.jpgTCR-activated CD4 T cell with cytoplasmic Bcl10 POLKADOTS that co-localize with LC3+ autophagosomes. Bcl10 (green) and LC3 (red) signals combine to produce yellow at the region of overlap. Blue is cell surface anti-CD4. The fluorescence image is overlayed on a grayscale DIC image.schaefer_lab_fig3.png

  Bioluminescence imaging of lyssavirus infection. Site and relative intensity of lyssavirus infection are visualized via a luminescence image overlaid on a CT scan.  We are using this technology to longitudinally trace lyssavirus infection and to assess efficacy of novel therapies.

Research:  Mechanisms of leukocyte activation in response to infectious agents and cancer

Our research is focused on investigating signaling events that regulate leukocyte activation. Although we have a longstanding interest in T cell receptor (TCR) activation of NF-κB, our work has more recently diversified to include studies of the innate response to a variety of pathogens and cancer.  Our experimental approach combines cutting-edge imaging technologies with biochemistry, cell biology, and in vivo models of infection and tumorigenesis. We are currently focusing on the following major projects:

 

  1. Elucidating the molecular mechanisms and subcellular organization of T cell receptor-regulated NF-κB signaling intermediates.
    Our published studies (Schaefer et al PNAS 2004; Rossman et al MBC 2006; Paul et al Immunity 2012; Paul et al., Science Signaling 2014) have documented that TCR stimulation results in the de novo formation of a cytoplasmic signaling structure that we have named the POLKADOTS signalosome. Both signal transmission to NF-κB and limitation of signal transmission by selective autophagy of the signaling adaptor, Bcl10, occur at this site. Currently, we are using “super-resolution” microscopy and other cutting-edge techniques to define nanoscale features of this complex, and to relate those features mechanistically to regulation of signaling. We are also beginning to investigate in more detail the biochemical pathway by which the TCR induces the autophagy of specific targets, such as Bcl10. This NIH-funded work is being conducted collaboratively with the groups of Dr. Wolgang Losert at the University of Maryland, Dr. You-Wen He at Duke University, and Dr. Thomas Conrads at the Women's Health Integrated Research Center.

 

  1. Pre-clinical models and novel therapeutics for infections by neurotropic viruses.
    In collaboration with our Microbiology and Immunology Department colleague, Dr. Christopher Broder, and with colleagues in the Department of Radiology, we are investigating pathogenesis of neurotropic viruses at the cellular and organism level. The current project emphasis in my lab is in vivo modeling of infection with Australian Bat Lyssavirus (ABLV), a rabies-like virus which can infect humans and livestock. We are using a luciferase-expressing form of this virus to track infection longitudinally in vivo. The long term goal of this work is to develop novel and broadly-effective therapies, which would have efficacy following establishment of virus infection in the central nervous system. This work is funded by a USU Program Project grant, and we are seeking NIH funding to continue these very interesting studies.

 

  1. Defining the role of macrophages in immunosuppression in lung cancer.
    In this project, our studies are directed toward better defining the role of macrophages in lung cancer-associated immunosuppression. Our long-term goal is to provide data suggesting novel immunotherapy approaches, which may be more broadly successful in lung cancer than current available therapies. This translational work is a collaborative effort with our USU colleague, Dr. Clifton Dalgard (Anatomy, Physiology, and Genetics) and Murtha Cancer Center/WRNNMC physicians Dr. Corey Carter and Dr. Karen Zeman. This project is funded by a grant from the Murtha Cancer Center. 
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