Drug-induced transcriptional modules in mammalian biology: implications for drug repositioning and resistance
Gespeichert in:
| 1. Verfasser: | |
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| Format: | Abschlussarbeit Buch |
| Sprache: | English German |
| Veröffentlicht: |
2013
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| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | Zsfassung in engl. und dt. Sprache |
| Beschreibung: | XVI, 159 S. Ill., graph. Darst. |
Internformat
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Datensatz im Suchindex
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| adam_text | IMAGE 1
CONTENTS
SUMMARY V
ZUSAMMENFASSUNG VII
LIST OF FIGURES XIII
LIST OF TABLES XVI
1 INTRODUCTION 1
1.1 PUBLICLY AVAILABLE DATA INFORMATION RESOURCES 3
1.1.1 THE CONNECTIVITY MAP: A COMPENDIUM OF DRUG-INDUCED GENE
EXPRESSION PROFILES 7
1.1.2 ICONIX DRUGMATRIX REFERENCE DATABASE 7
1.2 INTEGRATIVE APPROACHES FOCUSED ON GENE EXPRESSION COMPENDIA 8
1.3 UTILIZATION OF GENE EXPRESSION DATA IN THE ELUCATION OF DRUG
TOLERANCE . 9
1.4 DRUG REPOSITIONING: NOVEL THERAPEUTIC IMPLICATIONS FOR APPROVED
DRUGS 11
1.4.1 SYSTEMATIC DRUG REPOSITIONING USING LARGE-SCALE RESOURCES OF DRUGS
12
1.4.2 THE CONNECTIVITY MAP CONCEPT: CONNECTING DISEASES, DRUGS AND
GENES VIA EXPRESSION SIGNATURES 13
1.4.3 NETWORK ANALYSIS OF CMAP RESOURCE WITH IMPLICATIONS IN DRUG
REPURPOSING 15
1.4.4 LARGE-SCALE INTEGRATION OF DRUG AND DISEASE-ASSOCIATED MICROAR-
RAY STUDIES 17
1.5 DRUG PERTURBATIONS AS CHEMICAL TOOLS FOR BIOLOGICAL UNDERSTANDING
. 19
1.6 BICLUSTERING OF GENE EXPRESSION COMPENDIA: AN ALTERNATIVE TO
SIGNATUREBASED METHOD 20
XI
HTTP://D-NB.INFO/1032783052
IMAGE 2
2 A I M S A N D OBJECTIVES
2 3
3 MATERIALS A N D M E T H O D S 2 5
3.1 MICROARRAY DATA SOURCES AND PRE-PROCESSING 25
3.1.1 MICROARRAY RESOURCE OF DRUG-TREATED HUMAN CELL LINES 25
3.1.2 ICONIX DATAMATRIX: RESOURCE ON RAT LIVER EXPRESSION RESPONSE
IN DRUG-TREATED RATS 27
3.1.3 DISEASE-ASSOCIATED GENOME-WIDE EXPRESSION PROFILES 29
3.2 PAIRWISE SIMILARITY SCORE OF DRUGS 30
3.3 TRANSCRIPTIONAL REGULATION OF TARGETS UPON ITS MODULATION 31
3.4 IDENTIFICATION OF DRUG-INDUCED TRANSCRIPTIONAL MODULES 32
3.5 ASSESSMENT OF FUNCTIONAL COHERENCE OF TRANSCRIPTIONAL MODULES . . .
. 33
3.6 COMPARISON OF TRANSCRIPTIONAL MODULES ACROSS CELL TYPES AND
ORGANISMS 34
3.7 CHARACTERIZATION OF DRUG-INDUCED TRANSCRIPTIONAL MODULES 34
3.8 CELL VIABILITY ASSAYS 35
3.9 FUNCTIONAL CHOLESTEROL ASSAYS USING SIRNA KNOCKDOWNS 36
4 RESULTS A N D DISCUSSION 3 9
4.1 NORMALIZATION OF THE HETEROGENEOUS CONNECTIVITY MAP DATASET . . . .
39
4.2 CALCULATING DRUG-DRUG SIMILARITIES BASED ON DRUG-INDUCED EXPRESSION
PROFILES 41
4.2.1 ASSESSMENT OF SYSTEMATIC BIASES AND THEIR CORRECTION IN CMAP 42
4.2.2 BENCHMARKING DIPS SCORE AGAINST INDEPENDENT FEATURES OF DRUGS 44
4.2.3 DRUG-DRUG ASSOCIATIONS BASED ON DIPS SCORES WERE EMBEDDED
IN PUBLICLY AVAILABLE STITCH 46
4.3 DIFFERENTIAL EXPRESSION OF DRUG-INDUCED DRUG TARGETS 48
4.4 REPERTOIRE OF DRUG-INDUCED TRANSCRIPTIONAL MODULES IN HUMAN AND RAT
54
4.4.1 IDENTIFICATION OF DRUG-INDUCED TRANSCRIPTIONAL MODULES 54
4.4.2 CONSERVATION OF DRUG-INDUCED TRANSCRIPTIONAL MODULES ACROSS
HUMAN CELL LINES AND ORGANISMS 56
XII
IMAGE 3
4.4.3 CHARACTERIZATION OF GENE AND DRUG MEMBERS OF DRUG-INDUCED
MODULES 59
4.4.4 DRUG REPOSITIONING VIA DRUG-INDUCED MODULES: NOVEL CELL CYCLE
INHIBITORS AS POTENTIAL ANTI-TUMOR AGENTS 64
4.4.5 FUNCTIONAL DISCOVERY VIA DRUG-INDUCED MODULES: EXPERIMEN
TALLY VALIDATED NOVEL MODULATORS OF CELLULAR CHOLESTEROL HOME
OSTASIS 70
4.5 DRUG REPOSITIONING BASED ON ANTICORRELATED EXPRESSION PROFILES OF
DISEASE-DRUG RELATIONS 72
4.5.1 NOVEL ANTI-MIGRATORY DRUGS FOR METASTATIC COLORECTAL CANCER . . 76
5 CONCLUSIONS A N D OUTLOOK 8 1
5.1 THE ROLE OF DRUG-INDUCED TARGET REGULATION IN TOLERANCE DEVELOPMENT
. 83
5.2 DRUG REPURPOSING USING DRUG-INDUCED TRANSCRIPTIONAL MODULES . . . .
85
5.3 IMPLICATIONS FOR FURTHER RESEARCH 86
6 REFERENCES 89
A A P P E N D I X 107
A.L PUBLICATIONS 107
A. 2 ACKNOWLEDGEMENTS 108
A.3 ABBREVIATIONS 110
A.4 SUPPLEMENTARY FIGURES I L L
A.5 SUPPLEMENTARY TABLES 114
XIII
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| language | English German |
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| spelling | ̇Iskar, Murat Verfasser (DE-588)1030533385 aut Drug-induced transcriptional modules in mammalian biology implications for drug repositioning and resistance [presented by Murat İskar] 2013 XVI, 159 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Zsfassung in engl. und dt. Sprache Heidelberg, Univ., Diss., 2013 (DE-588)4113937-9 Hochschulschrift gnd-content DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=025720520&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | ̇Iskar, Murat Drug-induced transcriptional modules in mammalian biology implications for drug repositioning and resistance |
| subject_GND | (DE-588)4113937-9 |
| title | Drug-induced transcriptional modules in mammalian biology implications for drug repositioning and resistance |
| title_auth | Drug-induced transcriptional modules in mammalian biology implications for drug repositioning and resistance |
| title_exact_search | Drug-induced transcriptional modules in mammalian biology implications for drug repositioning and resistance |
| title_full | Drug-induced transcriptional modules in mammalian biology implications for drug repositioning and resistance [presented by Murat İskar] |
| title_fullStr | Drug-induced transcriptional modules in mammalian biology implications for drug repositioning and resistance [presented by Murat İskar] |
| title_full_unstemmed | Drug-induced transcriptional modules in mammalian biology implications for drug repositioning and resistance [presented by Murat İskar] |
| title_short | Drug-induced transcriptional modules in mammalian biology |
| title_sort | drug induced transcriptional modules in mammalian biology implications for drug repositioning and resistance |
| title_sub | implications for drug repositioning and resistance |
| topic_facet | Hochschulschrift |
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