Quantitative analysis of adenoviral vector modification of a cytokine-mediated cell death decision
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2006.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2008
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| Online Access: | http://dspace.mit.edu/handle/1721.1/35519 http://hdl.handle.net/1721.1/35519 |
| _version_ | 1826201577451421696 |
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| author | Miller, Kathryn Elizabeth |
| author2 | Douglas A. Lauffenburger. |
| author_facet | Douglas A. Lauffenburger. Miller, Kathryn Elizabeth |
| author_sort | Miller, Kathryn Elizabeth |
| collection | MIT |
| description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2006. |
| first_indexed | 2024-09-23T11:53:38Z |
| format | Thesis |
| id | mit-1721.1/35519 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T11:53:38Z |
| publishDate | 2008 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/355192019-04-10T11:39:39Z Quantitative analysis of adenoviral vector modification of a cytokine-mediated cell death decision Miller, Kathryn Elizabeth Douglas A. Lauffenburger. Massachusetts Institute of Technology. Dept. of Chemical Engineering. Massachusetts Institute of Technology. Dept. of Chemical Engineering. Chemical Engineering. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2006. Vita. Includes bibliographical references (leaves 91-102). Intracellular networks arise from complex interactions between proteins that relay signals and control cellular responses. Viruses, with limited genetic material, can modify network signals and change cell behavior. Replication-deficient viruses are used extensively as delivery vectors in clinical gene therapy and in molecular biology, but little is known about how the viral carrier itself contributes to cellular responses. In this thesis, we explored the link between viral vector modifications of signaling networks to changes in cellular phenotype. We approached this problem by studying a therapeutically relevant model in which an adenoviral vector (Adv) sensitizes human tumor epithelial cells to tumor necrosis factor (TNF)-induced apoptosis. We first measured TNF-stimulated signaling profiles over a range of Adv infection levels for a distribution of kinases centrally involved in the TNF signaling network. We then applied quantitative analytical techniques to determine the most important signals contributing to Adv-induced changes in TNF-mediated apoptosis. We experimentally derived a mathematical equation describing the saturation of anti-apoptotic Akt effector signaling in the presence of high levels of Adv infection, which could predict TNF-induced apoptosis in HT-29 cells. (cont.) However, the same equation did not apply in HeLa cells, suggesting that one-signal models are insufficient to account for complex network interactions. Therefore, we applied a systems-modeling approach to our Adv-TNF system and mathematically identified a multivariate signal-processing function sufficient to predict Adv-TNF induced apoptosis in both HT-29 cells and HeLa cells. The common-processing model identified critical Adv-induced cell-specific signaling modifications, and accurately predicted apoptosis following perturbation with pharmacological inhibitors of Akt and IKK. Thus, by combining experimental and computational approaches, this thesis has identified an important biological principle, common signal processing, for studying cell-specific responses to viral infections and rational drug therapies. by Kathryn E. Miller. Ph.D. 2008-01-10T17:25:36Z 2008-01-10T17:25:36Z 2006 2006 Thesis http://dspace.mit.edu/handle/1721.1/35519 http://hdl.handle.net/1721.1/35519 71825156 eng M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. http://dspace.mit.edu/handle/1721.1/35519 http://dspace.mit.edu/handle/1721.1/7582 102 leaves application/pdf Massachusetts Institute of Technology |
| spellingShingle | Chemical Engineering. Miller, Kathryn Elizabeth Quantitative analysis of adenoviral vector modification of a cytokine-mediated cell death decision |
| title | Quantitative analysis of adenoviral vector modification of a cytokine-mediated cell death decision |
| title_full | Quantitative analysis of adenoviral vector modification of a cytokine-mediated cell death decision |
| title_fullStr | Quantitative analysis of adenoviral vector modification of a cytokine-mediated cell death decision |
| title_full_unstemmed | Quantitative analysis of adenoviral vector modification of a cytokine-mediated cell death decision |
| title_short | Quantitative analysis of adenoviral vector modification of a cytokine-mediated cell death decision |
| title_sort | quantitative analysis of adenoviral vector modification of a cytokine mediated cell death decision |
| topic | Chemical Engineering. |
| url | http://dspace.mit.edu/handle/1721.1/35519 http://hdl.handle.net/1721.1/35519 |
| work_keys_str_mv | AT millerkathrynelizabeth quantitativeanalysisofadenoviralvectormodificationofacytokinemediatedcelldeathdecision |