Date of Award

5-13-2011

Document Type

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

Keywords

Aplastic Anemia, Notch, PKC Theta, T Cells, Th1

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.


Download

Share

COinS