Genomic analysis of hepatic insulin resistance
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2006.
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| Other Authors: | |
| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2008
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| Online Access: | http://dspace.mit.edu/handle/1721.1/33762 http://hdl.handle.net/1721.1/33762 |
| _version_ | 1811096309892907008 |
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| author | Raab, R. Michael |
| author2 | Gregory Stephanopoulos. |
| author_facet | Gregory Stephanopoulos. Raab, R. Michael |
| author_sort | Raab, R. Michael |
| collection | MIT |
| description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2006. |
| first_indexed | 2024-09-23T16:41:47Z |
| format | Thesis |
| id | mit-1721.1/33762 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T16:41:47Z |
| publishDate | 2008 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/337622019-04-10T11:39:53Z Genomic analysis of hepatic insulin resistance Raab, R. Michael Gregory Stephanopoulos. 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, February 2006. Includes bibliographical references (leaves 159-191). Type II Diabetes mellitus is a genetically complex disease characterized by insulin resistance in peripheral tissues, which results in simultaneous hyperglycemia and hyperinsulinemia. Because of the prevalence of type II diabetes, many researchers are investigating the genetics of glucose homeostasis, however, traditional mapping techniques have not been successful in determining all of the genes that regulate glycemia. To complement these efforts, we used DNA microarrays to find differentially expressed genes and combinatorial siRNA screening to investigate the effects of hepatic gene transcription during periods of high and low glucose production. This strategy provides a new approach to studying the molecular mechanisms of disease pathogenesis. Our investigations focused on discovering new genes that influence hepatic metabolism and glucose production. Hepatocytes help maintain whole body glycemia by providing glucose and other substrates during non-feeding periods. DNA microarrays containing 17,000 unique gene probes were used to study hepatic gene transcription during normal, insulin resistant, and fasting states in C57/BL/6J mice. We analyzed this data set using a combination of statistical and multivariate techniques to determine 41 different, genes that are differentially expressed and highly discriminatory of the treatment groups. (cont.) Hepatocytes perform many physiological roles, thus to investigate which genes from the microarray analysis affected hepatic metabolism, we developed combinatorial RNA-interference (RNAi) based gene silencing techniques. Using combinatorial siRNA screening, we silenced genes that were over-expressed within the microarray data set to study loss of function effects on hepatic metabolism, which was quantified by measuring intracellular metabolite concentrations in relevant metabolic pathways. Based upon the metabolite dependent clustering of experimental and control samples using Fisher Discriminant Analysis, four of the silenced genes had a significant effect on key metabolites involved in hepatic glucose output. Of these four genes, three were shown to influence hepatic glucose output in our primary cell model. by R. Michael Raab. Ph.D. 2008-02-28T16:20:22Z 2008-02-28T16:20:22Z 2005 2006 Thesis http://dspace.mit.edu/handle/1721.1/33762 http://hdl.handle.net/1721.1/33762 69019643 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/1721.1/33762 http://dspace.mit.edu/handle/1721.1/7582 191 leaves application/pdf Massachusetts Institute of Technology |
| spellingShingle | Chemical Engineering. Raab, R. Michael Genomic analysis of hepatic insulin resistance |
| title | Genomic analysis of hepatic insulin resistance |
| title_full | Genomic analysis of hepatic insulin resistance |
| title_fullStr | Genomic analysis of hepatic insulin resistance |
| title_full_unstemmed | Genomic analysis of hepatic insulin resistance |
| title_short | Genomic analysis of hepatic insulin resistance |
| title_sort | genomic analysis of hepatic insulin resistance |
| topic | Chemical Engineering. |
| url | http://dspace.mit.edu/handle/1721.1/33762 http://hdl.handle.net/1721.1/33762 |
| work_keys_str_mv | AT raabrmichael genomicanalysisofhepaticinsulinresistance |