Quantitative analysis of adenoviral vector modification of a cytokine-mediated cell death decision

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.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemical Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2006

Author dc:creator

• Miller, Kathryn Elizabeth

Advisor dc:contributor.advisor

• Douglas A. Lauffenburger.

• Chemical Engineering.

Statement dc:rights

• 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.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/35519
• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Identifier URI

http://dspace.mit.edu/handle/1721.1/35519

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/35519