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Quantitative analysis of cytokine-induced hepatocellular death in the context of hepatotoxic therapeutics

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dc.contributor.advisor Linda G. Griffith and Douglas A. Lauffenburger. en_US
dc.contributor.author Cosgrove, Benjamin D. (Benjamin David) en_US
dc.contributor.other Massachusetts Institute of Technology. Dept. of Biological Engineering. en_US
dc.date.accessioned 2011-02-23T14:31:44Z
dc.date.available 2011-02-23T14:31:44Z
dc.date.issued 2009 en_US
dc.identifier.uri http://hdl.handle.net/1721.1/61221
dc.description Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2009. en_US
dc.description "February 2009." Cataloged from PDF version of thesis. en_US
dc.description Includes bibliographical references (p. 161-178). en_US
dc.description.abstract Numerous therapeutics, such as viral gene therapy vectors, have unintended toxicity in part due to interactions with inflammatory cytokine signaling to elicit hepatocyte death, thus limiting their clinical use. Although much is known about how cytokines and certain therapeutics individually induce hepatotoxicity, there is little understanding of how they jointly regulate the complex cellular signaling network governing hepatocellular death. In this thesis, we explored the signaling mechanisms governing the cytokine-induced hepatocellular death in the context of adenoviral vector (Adv) infection and pharmaceutical compounds with idiosyncratic hepatotoxicity. Initially, we examined the role of autocrine and intracellular signaling pathways in governing the synergistic induction of hepatocyte apoptosis by the cytokine tumor necrosis factor-a (TNF) in the presence of Adv infection in a primary rat hepatocyte cell culture model. We demonstrated that Adv/TNF-induced hepatocyte apoptosis is regulated by a coupled and self-antagonizing autocrine signaling cascade involving the sequential release of anti-apoptotic transforming growth factor-a (TGF-a), pro-apoptotic interleukin- 1 a/p (IL-l a/), and anti-apoptotic IL- 1 receptor antagonist (IL- Ira). This three-part autocrine cascade regulates multiple intracellular signal pathways, including ERK and JNK, that serve to integrate TNF- and Adv-induced signals and govern the resultant hepatocellular death response. Following this, we demonstrated that numerous idiosyncratic hepatotoxins, whose hepatotoxicities are not evident in standard cell preclinical screening models, elicit synergistic induction of hepatocellular death upon multi-cytokine co-stimulation in primary rat and human hepatocyte cell culture models. We showed that this drugcytokine co-treatment model could be usefully scaled to the high-throughput demands of pharmaceutical screening while maintaining idiosyncratic hepatotoxicity prediction accuracy. To identify the signaling mechanisms regulating these drug/cytokine hepatocellular death synergies, we collected multi-pathway signal-response data compendia from two human hepatocyte donors. Through the use of partial least-squares regression modeling, we showed that hepatocytes integrate signals from four pathways -- ERK, Akt, mTOR, and p38 -- to specify their cell death responses to toxic drug/cytokine conditions and that accurate prediction of hepatocellular death responses can be made across human hepatocyte donors. Together, these findings demonstrate that cytokine-induced hepatocellular death in the context of hepatotoxic therapeutics is governed by integrated network activity of multiple autocrine and intracellular signaling pathways. en_US
dc.description.statementofresponsibility by Benjamin D. Cosgrove. en_US
dc.format.extent 178 p. en_US
dc.language.iso eng en_US
dc.publisher Massachusetts Institute of Technology en_US
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. en_US
dc.rights.uri http://dspace.mit.edu/handle/1721.1/7582 en_US
dc.subject Biological Engineering. en_US
dc.title Quantitative analysis of cytokine-induced hepatocellular death in the context of hepatotoxic therapeutics en_US
dc.type Thesis en_US
dc.description.degree Ph.D. en_US
dc.contributor.department Massachusetts Institute of Technology. Dept. of Biological Engineering. en_US
dc.identifier.oclc 701386080 en_US


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