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The roles of Notch1 and PKC-Θ in immune mediated bone marrow failure

Justine E Roderick, University of Massachusetts Amherst

Abstract

We sought to evaluate the individual contributions of Notch1 and PKC-Theta to disease progression in a mouse model of immune-mediated bone marrow failure and to define a mechanism for their potential cellular cooperation. We transferred parental bulk splenocytes into F1-hybrid recipients to induce a robust immune-mediated bone marrow failure (BMF) that we could partially rescue by administering a pharmacological inhibitor of Notch activation. Transferring splenocytes from PKC-Theta deficent animals did not induce disease, and treating animals with a pharmacological inhibitor of PKC-Theta also provided full protection from disease. We found that inhibiting Notch1 resulted in PKC-Theta down-regulation, and blocking PKC-Theta reduced Notch1 activation. We further evaluated this cross-talk using in vitro studies that demonstrated direct interaction of Notch1 and PKC-Theta following stimulation through the T cell receptor together with co-stimulation through CD28. Our data suggest that both Notch1 and PKC-Theta contribute to disease progression in our mouse model of immune-mediated bone marrow failure. Furthermore, we can demonstrate physical interactions between Notch1, members of the T cell signalosome and PKC-Theta that are essential to mediating full activation of T cells following signaling through the TCR and CD28. Notch1 and/or PKC-Theta may represent novel therapeutic targets in the treatment of bone marrow failure.

Subject Area

Immunology

Recommended Citation

Roderick, Justine E, "The roles of Notch1 and PKC-Θ in immune mediated bone marrow failure" (2011). Doctoral Dissertations Available from Proquest. AAI3465077.
https://scholarworks.umass.edu/dissertations/AAI3465077

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