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Quantitative analysis of TLR-4-mediated cell responses in murine macrophages

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dc.contributor.advisor Douglas A. Lauffenburger and David B. Schauer. en_US Wu, Rongcong en_US
dc.contributor.other Massachusetts Institute of Technology. Biological Engineering Division. en_US 2009-03-16T19:54:54Z 2009-03-16T19:54:54Z 2008 en_US 2008 en_US
dc.description Thesis (S.M.)--Massachusetts Institute of Technology, Biological Engineering Division, 2008. en_US
dc.description Vita. en_US
dc.description Includes bibliographical references (p. 82-89). en_US
dc.description.abstract TLR-4 is essential in host defense against bacterial infection. By recognition of specific pathogen-associated molecular patterns such as lipopolysaccharide (LPS), TLR-4 can in tandem initiate a pair of downstream signaling pathways to regulate cytokine/chemokine release, endotoxin tolerance and apoptosis, which have been suggested to directly or indirectly participate in the regulation of innate and adaptive immune responses. However, little is known about their detailed signal-response relationships. In this thesis, we sought to identify these potential signal-response relationships in RAW264.7 cells through systematic analysis. We first measured LPS stimulated dynamic signaling profiles over a range of an inhibitor of p38 MAPK, SB202190 concentrations for a distribution of kinases centrally involved in TLR-4 signaling network. We then applied quantitative analytical approaches to determine the most important signals or signal combinations contributing to induction of either IL-6 and TNF-ao secretion or apoptosis and construct their corresponding predictive mathematical models. Particularly, we found that the partial least squares regression (PLSR) models built using the ratio of phosphorylated Jun N-terminal kinase (JNK) and extracellular signal regulated kinase (ERK) predicted LPS plus SB202190-induced apoptosis accurately even following perturbation with pharmacological inhibitors of JNK and ERK. Thus, by combining experimental and computational approaches, this thesis has proposed two new potential targets, JNK and ERK, for development of drug therapies against bacterial infection. en_US
dc.description.statementofresponsibility by Rongcong Wu. en_US
dc.format.extent 89 p. en_US
dc.language.iso eng en_US
dc.publisher Massachusetts Institute of Technology en_US
dc.rights MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. en_US
dc.rights.uri en_US
dc.subject Biological Engineering Division. en_US
dc.title Quantitative analysis of TLR-4-mediated cell responses in murine macrophages en_US
dc.type Thesis en_US S.M. en_US
dc.contributor.department Massachusetts Institute of Technology. Biological Engineering Division. en_US
dc.identifier.oclc 302282746 en_US

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