Date of Award
5-13-2011
Document type
dissertation
Access Type
Open Access Dissertation
Degree Name
Doctor of Philosophy (PhD)
Degree Program
Animal Biotechnology & Biomedical Sciences
First Advisor
Lisa M. Minter
Second Advisor
Barbara A. Osborne
Third Advisor
Juan Anguita
Subject Categories
Animal Sciences
Abstract
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.
DOI
https://doi.org/10.7275/2176856
Recommended Citation
Roderick, Justine E., "The Roles of Notch1 and PKC-Θ in Immune Mediated Bone Marrow Failure" (2011). Open Access Dissertations. 416.
https://doi.org/10.7275/2176856
https://scholarworks.umass.edu/open_access_dissertations/416