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The Roles of Notch1 and PKC-Θ in Immune Mediated Bone Marrow Failure

We sought to evaluate the individual contributions of Notch1 and PKC-ζ 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--ζ-/- animals did not induce disease, and treating animals with a pharmacological inhibitor of PKC-ζ also provided full protection from disease. We found that inhibiting Notch1 resulted in PKC-ζ down-regulation, and blocking PKC-ζ reduced Notch1 activation, possibly within a positive feedback loop. Our data suggest that both Notch1 and PKC-ζ contribute to disease progression in our mouse model of immune-mediated bone marrow failure. Furthermore, additional findings from the lab demonstrated physical interactions between Notch1, members of the T cell signalosome and PKC-ζ that are essential to mediating full activation of T cells following signaling through the TCR and CD28. Notch1 and/or PKC-ζ may represent novel therapeutic targets in the treatment of bone marrow failure.

Identiferoai:union.ndltd.org:UMASS/oai:scholarworks.umass.edu:open_access_dissertations-1410
Date13 May 2011
CreatorsRoderick, Justine E
PublisherScholarWorks@UMass Amherst
Source SetsUniversity of Massachusetts, Amherst
Detected LanguageEnglish
Typetext
Formatapplication/pdf
SourceOpen Access Dissertations

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