Activin signaling as a molecular target in antidepressant therapy: = Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie
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| Main Author: | |
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| Format: | Thesis Book |
| Language: | English |
| Published: |
2015
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| Subjects: | |
| Online Access: | Inhaltsverzeichnis |
| Physical Description: | 147 S. Ill., graph. Darst. |
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| 245 | 1 | 0 | |a Activin signaling as a molecular target in antidepressant therapy |b = Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie |c vorgelegt von Andrea Stephanie Link |
| 246 | 1 | 1 | |a Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie |
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| 650 | 0 | 7 | |a Activin |0 (DE-588)4490155-0 |2 gnd |9 rswk-swf |
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Record in the Search Index
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|---|---|
| adam_text | ACTIVIN SIGNALING
AS A MOLECULAR TARGET IN
ANTIDEPRESSANT THERAPY
DER ACTIVIN-SIGNALWEG ALS MOLEKULARES ZIEL ANTIDEPRESSIVER THERAPIE
DER NATURWISSENSCHAFTLICHEN FA KU I TAT
DER FRIEDRICH-ALEXANDER-UNIVERSITAT ERLANGEN-NUMBERG
ZUR
ERLANGUNG DES DOKTORGRADES DR. RER. NAT.
VORGELEGT VON
ANDREA STEPHANIE LINK
AUS FURTH
HTTP://D-NB.INFO/1072041022
TABLE OF CONTENTS
TABLE OF CONTENTS
1 SUMMARY/ ZUSAMMENFASSUNG 4
1.1 SUMMARY 4
1.2 ZUSAMMENFASSUNG 6
2 INTRODUCTION 8
2.1 ACTIVIN A-A MEMBER OF THE TGF-P FAMILY 8
2.2 ACTIVIN ISOFORMS AND SIGNAL TRANSDUCTION 8
2.3 TRANSCRIPTIONAL REGULATION OF TGF-FJ/ACTIVIN TARGET GENES BY SMAD
COMPLEXES 10
2.4 NEGATIVE REGULATORS OF TGF-|3/ACTIVIN SIGNALING 11
2.5 ROLE OF ACTIVIN A IN THE CENTRAL NERVOUS SYSTEM 12
2.5.1 EXPRESSION AND FUNCTION OF ACTIVIN A DURING NEURONAL DEVELOPMENT
AND IN
PERINATAL BRAIN INJURY 12
2.5.2 ACTIVIN A AS A NEUROTROPHIC AND NEUROPROTECTIVE FACTOR IN THE CNS
14
2.5.3 ACTIVIN A AS A MODULATOR OF EXCITATORY AND INHIBITORY SIGNALING IN
THE CNS 16
2.5.4 ROLE OF ACTIVIN A IN ANXIETY AND DEPRESSION 18
2.6 DEPRESSION AND CURRENT TREATMENT OPTIONS 20
2.7 AIM OF THE THESIS 21
3 RESULTS 23
3.1 ACTIVIN AS A TARGET OF ANTIDEPRESSANT THERAPY AND ENVIRONMENTAL
STIMULATION 23
3.1.1 REGULATION OF ACTIVIN SIGNALING BY ANTIDEPRESSANT TREATMENT 23
3.1.2 STRONG INDUCTION OF ACTIVIN A, BUT NOT OTHER TGF-P
SUBFAMILY MEMBERS, IN THE
HIPPOCAMPUS BY ECS 25
3.1.3 ENHANCED INHBA EXPRESSION DURING ENVIRONMENTAL ENRICHMENT 28
3.2 IDENTIFICATION OF ACTIVIN TARGET GENES 30
3.2.1 GENOME-WIDE COMPARISON OF GENE REGULATION IN THE HIPPOCAMPUS
BETWEEN
WILD-TYPE AND DNACTRIB MICE AFTER ECS 30
3.2.2 IDENTIFICATION OF NOVEL SMAD2/3 TARGET GENES IN THE HIPPOCAMPUS
AFTER ECS BY
CHIP 37
3.2.3 ANALYSIS OF PMEPAL MRNA EXPRESSION AND REGULATION IN THE BRAIN 41
3.2.4 CONSERVED REGULATION OF PMEPA1 BY ACTIVIN IN HUMAN NEURONS 41
3.2.5 CHARACTERIZATION OF KDM6B AS A NOVEL ACTIVIN TARGET GENE 43
3.2.6 INDUCTION OF KDM6B MRNA BY ACTIVIN IN HUMAN NEURONS 46
3.2.7 NO CHANGE IN GLOBAL H3K27 TRIMETHYLATION AFTER ECS 46
3.2.8 SEARCH FOR POTENTIAL KDM6B TARGET GENES 49
1
TABLE OF CONTENTS
3.3 DEVELOPMENTAL REGULATION OF ACTIVIN AND OTHER COMPONENTS OF THE
TGF-F)
SIGNALING
PATHWAY AFTER ECS 52
3.4 GENERATION OF CAACTRIB-TRANSGENIC MICE 58
3.4.1 VERIFICATION OF THE FUNCTIONALITY OF THE CAACTRIB
CONSTRUCT 58
3.4.2 CHARACTERIZATION OF CAACTRIB-TRANSGENIC MICE 60
3.4.3 DECREASED GABA
TONUS IN THE HIPPOCAMPUS OF CAACTRIB
MICE 61
3.4.4 DIFFERENTIAL EXPRESSION OF OXIDATION RESISTANCE 1 (OXRL) IN FLOXED
AND CAACTRIB
MICE 62
3.4.5 OXRL GENE AS POTENTIAL INTEGRATION SITE OF THE CAMKIIA-CRE
RECOMBINASE
TRANSGENE 65
4 DISCUSSION 66
4.1 RESPONSIVENESS OF ACTIVIN SIGNALING TO ANTIDEPRESSANT THERAPY 66
4.2 MASSIVE AND REGION-SPECIFIC UP-REGULATION OF ACTIVIN SIGNALING AFTER
ECS 66
4.3 NO EFFECT OF CHRONIC FLUOXETINE TREATMENT ON ACTIVIN PA EXPRESSION
67
4.4 ENHANCED ACTIVIN SIGNALING DURING ENVIRONMENTAL ENRICHMENT 68
4.5 IDENTIFICATION AND CHARACTERIZATION OF PMEPAL AND KDM6B AS NOVEL
HIPPOCAMPAL
TARGET GENES OF ACTIVIN SIGNALING 69
4.6 PMEPAL AS A NOVEL ACTIVIN TARGET GENE 70
4.7 KDM6B AS A NOVEL
ACTIVIN TARGET GENE 71
4.7.1 KDM6B IN NEURAL DEVELOPMENT 71
4.7.2 KDM6B EXPRESSION AND REGULATION IN (HE ADULT BRAIN 72
4.7.3 TARGETING OF THE HISTONE MARK H3K27ME3 IN DEPRESSION-RELATED
PROCESSES... 73
4.7.4 A POTENTIAL ANTIDEPRESSANT MECHANISM OF ACTIVIN/KDM6B SIGNALING 74
4.7.5 SEARCH FOR COMMON SMAD2/3/KDM6B TARGET GENES 75
4.8 AGE-DEPENDENT REGULATION OF ECS-INDUCIBLE GENES
IN THE HIPPOCAMPUS 78
4.8.1 DEVELOPMENTAL REGULATION OF ACTIVIN SIGNALING AFTER ECS 78
4.8.2 DEVELOPMENTAL REGULATION OF FURTHER, WELL-KNOWN ECS-INDUCIBLE
GENES 80
4.9 GENERATION OF CAACTRIB-TRANSGENIC MICE FOR THE INVESTIGATION OF
CONSTITUTIVELY-ACTIVE
ACTIVIN SIGNALING 83
5 CONCLUSION 84
6 METHODS AND MATERIAL 85
6.1 MOLECULAR BIOLOGY 85
6.1.1 REVERSE TRANSCRIPTION QUANTITATIVE REAL TIME PCR (RT-QPCR) 85
6.1.2 MICROARRAY 86
6.1.3 PREPARATION OF PROTEIN LYSATES 86
2
TABLE OF CONTENTS
6.1.4 WESTERNBLOT 86
6.1.5 CHROMATIN IMMUNOPRECIPITATION (CHIP) 87
6.2 CELL CULTURE 91
6.2.1 CELL LINES 91
6.2.2 TRANSFECTION 92
6.2.3 STARVATION ASSAY 92
6.3 ANIMAL EXPERIMENTS 92
6.3.1 MICE 92
6.3.2 ENVIRONMENTAL ENRICHMENT (EE) 93
6.3.3 APPLICATION OF ELECTROCONVULSIVE SEIZURES (ECS) 93
6.3.4 FLUOXETINE TREATMENT 94
6.4 HISTOLOGICAL METHODS 94
6.4.1 IN SITU HYBRIDIZATION 94
6.4.2 IMMUNOFLUORESCENCE 97
6.4.3 NISSL STAINING 98
6.5 GENERATION OF TRANSGENIC MICE 98
6.5.1 PLASMID CONSTRUCTION 98
6.5.2 VERIFICATION OF PLASMID FUNCTIONALITY 101
6.5.3 MOUSE MATING AND GENOTYPING 102
6.6 STATISTICAL ANALYSIS 104
6.7 MATERIAL 105
6.7.1 PRIMERS AND ANTIBODIES 105
6.7.2 BUFFERS AND SOLUTIONS 110
6.7.3 MATERIAL LISTS 115
7 REFERENCES 121
8 ABBREVIATIONS 139
9 LIST OF FIGURES 142
10 LIST OF TABLES 144
11 DECLARATION 145
12 ACKNOWLEDGEMENTS 147
3
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| dewey-ones | 610 - Medicine and health |
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| dewey-search | 610 |
| dewey-sort | 3610 |
| dewey-tens | 610 - Medicine and health |
| discipline | Medizin |
| format | Thesis Book |
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| spelling | Link, Andrea Stephanie Verfasser (DE-588)1069227307 aut Activin signaling as a molecular target in antidepressant therapy = Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie vorgelegt von Andrea Stephanie Link Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie 2015 147 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Erlangen-Nürnberg, Univ., Diss., 2015 Signalkette (DE-588)4409935-6 gnd rswk-swf Inhibition (DE-588)4273127-6 gnd rswk-swf Antidepressivum (DE-588)4002263-8 gnd rswk-swf Activin (DE-588)4490155-0 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Antidepressivum (DE-588)4002263-8 s Activin (DE-588)4490155-0 s Signalkette (DE-588)4409935-6 s Inhibition (DE-588)4273127-6 s DE-604 DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027918783&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Link, Andrea Stephanie Activin signaling as a molecular target in antidepressant therapy = Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie Signalkette (DE-588)4409935-6 gnd Inhibition (DE-588)4273127-6 gnd Antidepressivum (DE-588)4002263-8 gnd Activin (DE-588)4490155-0 gnd |
| subject_GND | (DE-588)4409935-6 (DE-588)4273127-6 (DE-588)4002263-8 (DE-588)4490155-0 (DE-588)4113937-9 |
| title | Activin signaling as a molecular target in antidepressant therapy = Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie |
| title_alt | Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie |
| title_auth | Activin signaling as a molecular target in antidepressant therapy = Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie |
| title_exact_search | Activin signaling as a molecular target in antidepressant therapy = Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie |
| title_full | Activin signaling as a molecular target in antidepressant therapy = Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie vorgelegt von Andrea Stephanie Link |
| title_fullStr | Activin signaling as a molecular target in antidepressant therapy = Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie vorgelegt von Andrea Stephanie Link |
| title_full_unstemmed | Activin signaling as a molecular target in antidepressant therapy = Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie vorgelegt von Andrea Stephanie Link |
| title_short | Activin signaling as a molecular target in antidepressant therapy |
| title_sort | activin signaling as a molecular target in antidepressant therapy der activin signalweg als molekulares ziel antidepressiver therapie |
| title_sub | = Der Activin-Signalweg als molekulares Ziel antidepressiver Therapie |
| topic | Signalkette (DE-588)4409935-6 gnd Inhibition (DE-588)4273127-6 gnd Antidepressivum (DE-588)4002263-8 gnd Activin (DE-588)4490155-0 gnd |
| topic_facet | Signalkette Inhibition Antidepressivum Activin Hochschulschrift |
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