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ANALYSIS OF HIGH-DENSITY OLIGONUCLEOTIDE GENE EXPRESSION
DATA FOR DISSECTING AGING PATHWAYS
by
Christina Curtis
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR BIOLOGY)
August 2007
Copyright 2007 Christina Curtis
Object Description
| Title | Analysis of high-density oligonucleotide gene expression data for dissecting aging pathways |
| Author | Curtis, Christina |
| Author email | ccurtis@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular & Computational Biology |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2007-06-18 |
| Date submitted | 2007 |
| Restricted until | Restricted until 26 July 2009. |
| Date published | 2009-07-26 |
| Advisor (committee chair) | Tavaré, Simon |
| Advisor (committee member) |
Tower, John Bottjer, David |
| Abstract | Microarray technology has revolutionized the study of gene expression by allowing the entire transcriptome to be simultaneously assayed. Affymetrix GeneChips® are a popular type of high-density oligonucleotide expression array used by thousands of researchers worldwide. Despite continual advances in optimizing this technology to yield accurate gene expression measures, numerous theoretical and statistical considerations remain to be addressed. At the most fundamental level, the mechanism of probe-target hybridization is not well understood in the context of microarrays, that is, in a solution-surface environment as opposed to solely in solution. Since non-specific hybridization and probe-specific effects can lead to imprecise and inaccurate results at downstream stages of data analysis, it is important to give due consideration to these effects. This subject is the focus of the first section of this dissertation, which describes the experimental validation of a detailed physical model of probe-target hybridization. The results of this study explain the mysterious difference in saturation intensities for Affymetrix GeneChip® arrays and provide insight into the theoretical and statistical modeling of microarray hybridization signals. The second section describes the application of Affymetrix GeneChip® technology to study the molecular mechanisms of aging in the model organisms D. melanogaster and C. elegans. Specifically, three studies are described.; In the first, the transcriptional outputs of long-lived MnSOD over-expressing Drosophila were examined and suggest that MnSOD may mediate beneficial changes in nuclear gene expression by a retrograde signal of increased hydrogen peroxide. Additionally, by cross-species comparison to long-lived C. elegans insulin-like growth factor receptor (daf-2) mutants, a small set of conserved longevity-promoting genes were identified, suggesting that at least some of the mechanisms involved in lifespan extension are common to multiple interventions. In a separate study, Drosophila were subject to various forms of stress, each of which drastically diminishes lifespan, and their genome-wide expression patterns were compared to that of normal aging to determine their contribution to the aging process. Third, the transcriptional profiles of C. elegans daf-2 mutants reared at different temperatures were examined and used to identify novel genes that influence longevity, and to generate new hypotheses concerning pathways that likely influence aging. |
| Keyword | microarray; probe-target hybridization; aging; Drosophila; C. elegans |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m668 |
| Rights | Curtis, Christina |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Curtis-20070726 |
| Archival file | uscthesesreloadpub_Volume51/etd-Curtis-20070726.pdf |
Description
| Title | Page 1 |
| Full text | ANALYSIS OF HIGH-DENSITY OLIGONUCLEOTIDE GENE EXPRESSION DATA FOR DISSECTING AGING PATHWAYS by Christina Curtis A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR BIOLOGY) August 2007 Copyright 2007 Christina Curtis |
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