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Cellular Targets and Modes of Action for Proteasome Inhibitors in the B-Cell Lineage / Trini A Ochoa.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Ochoa, Trini A., author.
- Language:
- English
- Subjects (All):
- Immunology.
- Pathology.
- Virology.
- Immunology--Penn dissertations.
- Penn dissertations--Immunology.
- Local Subjects:
- Immunology.
- Pathology.
- Virology.
- Immunology--Penn dissertations.
- Penn dissertations--Immunology.
- Physical Description:
- 1 online resource (120 pages)
- Contained In:
- Dissertations Abstracts International 85-03B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Language Note:
- English
- Summary:
- Humoral immunity is a critical component of the adaptive immune system and provides protection through the generation of antibodies. In the context of disease, plasma cells that are malignant, self-reactive, or alloreactive in transplantation, can be detrimental to the health of the host. Although proteasome inhibition entered the clinic with substantial success over 2 decades ago, resistance to therapy develops in most settings and improvements on this life-saving therapy may be enhanced by understanding its mechanisms of action. In Chapter 2, we identified a mechanism of action in early activated B cells that is mediated by the tumor suppressor p53 in response to BTZ. Furthermore, p53 potentiation at proliferative stages of B cell differentiation was able to promote apoptosis, further implicating its activity in BTZ-induced apoptosis. Finally, we found that inhibition of the E3-ligases MDM2 and the APC/C with nutlin3a and proTAME, respectively, was sufficient to induce apoptosis and prevent B cell differentiation into plasma cells. In Chapter 3, we identified a preferential reduction of newly-formed plasma cells over their longer-lived counterparts in response to BTZ treatment. We found that acute doses of BTZ depleted most plasma cells with a small surviving population of cells with a B220- Bim- phenotype, suggesting that upstream regulators of Bim activity might be involved in BTZ-induced cell death. To that point, we tested the role of the transcription factor CHOP in mediating BTZ-induced cell death in plasma cells and identified a modest rescue effect. Collectively, these studies provide novel insights into the mechanisms of action of BTZ-induced cell death in B lineage cells at multiple stages of differentiation.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
- Advisors: Allman, David M.; Committee members: Oliver, Paula M.; Cancro, Michael P.; Beiting, Daniel P.; Eisenlohr, Laurence C.
- Department: Immunology.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798380384810
- Access Restriction:
- Restricted for use by site license.
- This item is not available from ProQuest Dissertations & Theses.
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