Effects of central nervous system-specific constitutive Tissue Inhibitor of Matrix Metalloproteinase-1 (Timp1)-expression in mice under physiological and pathological conditions:
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| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
2013
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| Beschreibung: | XI, 210 S. Ill., graph. Darst. 30 cm |
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| adam_text | EFFECTS OF CENTRAL NERVOUS SYSTEM-SPECIFIC CONSTITUTIVE TISSUE
INHIBITOR OF MATRIX METALLOPROTEINASE-1 (TIMPL)-EXPRESSION IN MICE
UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS
INAUGURAL THESIS TO THE ACQUISITION OF THE
DOCTOR S DEGREE
*
AT THE FACULTY FOR BIOLOGY,
ALBERT-LUDWIGS-UNIVERSITY FREIBURG IM BREISGAU
SUBMITTED BY
GIOIA ALTHOFF RUHLMANN
BORN IN BASEL, SWITZERLAND
NUR
BESCHRANKT ML
DEN
AUSTAUSCH
FREIBURG IM BREISGAU
16/12/2013
HTTP://D-NB.INFO/1052563503
INDEX
SUMMARY 1
I. INTRODUCTION 3
1. TISSUE INHIBITOR OF MATRIX METALLOPROTEINASES (TIMP) 3
1.1. STRUCTURE 3
1.2. FUNCTION 5
1.2.1. MMP-DEPENDENT ACTIVITIES 5
1.2.2. MMP-INDEPENDENT ACTIVITIES 7
1.2.2.1. PROMOTION OF CELL GROWTH 7
1.2.2.2. ANTI-APOPTOTIC ACTIVITY... 8
1.2.2.3. GROWTH-INHIBITORY ACTIVITY 10
1.2.2.4. IDENTIFICATION OF TIMP RECEPTORS 10
1.3. TISSUE DISTRIBUTION 11
2. TISSUE INHIBITOR OF MATRIX METALLOPROTEINASE 1 IN THE CENTRAL NERVOUS
SYSTEM 13
2.1. TIMP1 EXPRESSION UNDER PHYSIOLOGICAL CONDITIONS 14
2.2. TIMP1 EXPRESSION UNDER PATHOLOGICAL CONDITIONS 14
3. CENTRAL NERVOUS SYSTEM (CNS) 16
3.1. DEVELOPMENT 16
3.2. MACROSCOPIC ASPECT OF MOUSE CEREBELLAR DEVELOPMENT 19
3.3. MYELENCEPHALON AND SPINAL CORD 22
4. CNS: TO BE OR NOT TO BE IMMUNE PRIVILEGED 25
4.1. DEFINITION OF IMMUNE PRIVILEGE 25
4.2. CNS ANTIGEN PRESENTATION 27
4.2.1. BLOOD-BRAIN-BARRIER 28
4.2.2. ANTIGEN-PRESENTING CELLS 31
4.2.3. MICROGLIA CELLS 32
5. CNS AUTOIMMUNE DISEASES 34
5.1. MULTIPLE SCLEROSIS 34
5.2. EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 38
6. AIM OF THE STUDY 43
II. MATERIALS AND METHODS 44
1. MOUSE MODELS 44
1.1. GENERATION OF TIMP-1 TRANSGENIC MICE 44
1.2. GENERATION OF TIMP-1 TRANSGENIC RAG2 KO MICE 45
2. CHARACTERIZATION OF THE TIMP-1 TRANSGENIC MOUSE LINES 46
2.1. HISTOLOGY AND IMMUNOHISTOCHEMISTRY 46
2.2. RNA PREPARATION 47
2.3. ORGAN SURVEY 47
2.4. PROTEIN PREPARATION AND ENZYME-LINKED IMMUNOABSORBENT ASSAY (ELISA)
48
2.5.
IN SITU
HYBRIDIZATION 48
3. INDUCTION OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE) 48
4. RNASE PROTECTION ASSAY 49
5. IN SITU ZYMOGRAPHY 50
6. MICROARRAY ASSAY 50
7. BEHAVIOURAL TESTS 50
7.1. PLACE NAVIGATION AND REVERSAL NAVIGATION IN THE WATER-MAZE 51
7.1.1. PROCEDURE 52
7.1.2. GOAL POSITION AND START POINTS 53
7.2. OPEN FIELD TEST 55
7.3. LIGHT-DARK TRANSITION TEST 55
7.4. ELEVATED NULL-MAZE 56
7.5. EMERGENCE TEST AND NOVEL OBJECT TESTS 57
7.6. ROTAROD TEST 59
7.7. STATISTICAL MODEL 59
IX
INDEX
RESULTS: 61
III. MMP-DEPENDENT ROLE OF TIMP1 IN MICE CNS 61
1. CHARACTERIZATION OF T1F10, -F18 AND -F60 MOUSE LINES 61
1.1. EXPRESSION PATTERN OF TRANSGENIC TIMPL 61
1.2. MORPHOLOGY AND GELATINOLYTIC ACTIVITY 65
1.3. ANALYSIS OF MMP GENE REGULATION 69
2. BEHAVIOURAL ANALYSIS 71
3. INDUCTION OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE) 73
3.1. TRANSGENIC EXPRESSION OF
TIMPL
ALTERS THE COURSE OF EAE 73
3.2. HIGH DOSES OF TIMPL CAUSE PERIVASCULAR ACCUMULATION OF LYMPHOCYTES
77
IV. TRANSGENIC TIMP1 MOUSE LINES WITH INFLAMMATORY PHENOTYPE... 83
1. CEREBRAL EXPRESSION OF TIMPL IN T1F2B AND T1F11 MOUSE LINES 83
2. CHARACTERIZATION OF THE T1 F2B MOUSE LINE 88
2.1. BEHAVIORAL AND MORPHOLOGICAL PHENOTYPE OF THE T1 F2B MICE 88
2.2. CEREBELLAR ATROPHY AND MASSIVE CELL DEATH 93
3. CHARACTERIZATION OF THE
T1F11 MOUSE LINE 98
3.1. MORPHOLOGICAL PHENOTYPE OF THE T1F11 MOUSE LINE 98
3.2. AGGRAVATED COURSE OF EAE IN THE T1F11 MOUSE LINE 99
3.3. EAE SEVERITY IS RELATED TO ENHANCED INFLAMMATION IN T1F11 MICE 101
4. IDENTIFICATION OF TIMPL INDUCED MMP-INDEPENDENT PATHWAYS 105
4.1. MICROARRAY ASSAY 106
4.1.1. TRANSCRIPTION EFFECTORS AND GROWTH FACTORS 107
4.1.2. MOLECULAR AND CELLULAR FUNCTIONS 110
4.1.3. INTERFERON RELATED FACTORS (IRFS) 113
4.1.4. INFLAMMATION RELATED GENES 116
4.1.4.1. ANTIGEN PRESENTATION 116
4.1.4.2. IMMUNE SIGNALING PATHWAYS 118
4.2. T1 F2B MOUSE LINE 126
4.2.1. TIMPL AND POTENTIAL TIMPL RECEPTOR 126
4.2.2. STAT
-FAMILY T RANSCRIPTION FACTORS 128
4.2.3. APOPTOSIS-RELATED GENES 129
4.2.4. INFLAMMATORY MARKERS AND
CHEMOKINES 131
4.3. T1F11 MOUSE LINE 132
4.3.1. ACUTE AND CHRONIC INFLAMMATION IN THE T1F11 EAE
MOUSE MODEL 134
4.3.2. EXPRESSION OF LYMPHOCYTE SPECIFIC MARKERS 135
4.3.3. SIGNALING CASCADES INVOLVING STATS AND IRFS 142
V. WORK IN PROGRESS 146
1. CD63 MOUSE LINE 146
1. PRIMARY CELL CULTURES 146
2. LOCALIZATION OF THE TRANSGENE INTEGRATION IN THE GENOME OF T1
F2B AND T1F11
MOUSE LINES 147
1. T1F2B MOUSE LINE 147
2. T1F11 MOUSE LINE 147
VI. DISCUSSION 148
1. THE MMP-INHIBITORY FUNCTION OF TIMP1 LEADS TO NEUROPROTECTION 148
2. A MMP-INDEPENDENT FUNCTION OF TIMP1
IN THE CONTEXT OF NEUROINFLAMMATION?...
152
3. APOPTOSIS-RELATED CEREBELLAR ATROPHY 152
3.1. IT TAKES TWO TO TANGO: APOPTOSIS AND PHAGOCYTOSIS 155
3.2. INFLAMMATION: CAUSE OR CONSEQUENCE? 156
4. CD63-TIMP1 TANDEM AND POTENTIAL SIGNALING CASCADES 160
APPENDIX 1: BEHAVIORAL ANALYSIS OF TIMP-1 TRANSGENIC MICE 163
X
INDEX
APPENDIX 2: MICROARRAY ASSAY 176
ABREVIATIONS 185
TABLES 190
FIGURES 191
LITTERATURE 194
XI
|
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| author | Althoff Ruhlmann, Gioia |
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| dewey-full | 570 610 |
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| dewey-ones | 570 - Biology 610 - Medicine and health |
| dewey-raw | 570 610 |
| dewey-search | 570 610 |
| dewey-sort | 3570 |
| dewey-tens | 570 - Biology 610 - Medicine and health |
| discipline | Biologie Medizin |
| format | Thesis Book |
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| spelling | Althoff Ruhlmann, Gioia Verfasser (DE-588)1050990005 aut Effects of central nervous system-specific constitutive Tissue Inhibitor of Matrix Metalloproteinase-1 (Timp1)-expression in mice under physiological and pathological conditions submitted by Gioia Althoff Ruhlmann 2013 XI, 210 S. Ill., graph. Darst. 30 cm txt rdacontent n rdamedia nc rdacarrier Freiburg (Breisgau), 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=027501328&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Althoff Ruhlmann, Gioia Effects of central nervous system-specific constitutive Tissue Inhibitor of Matrix Metalloproteinase-1 (Timp1)-expression in mice under physiological and pathological conditions |
| subject_GND | (DE-588)4113937-9 |
| title | Effects of central nervous system-specific constitutive Tissue Inhibitor of Matrix Metalloproteinase-1 (Timp1)-expression in mice under physiological and pathological conditions |
| title_auth | Effects of central nervous system-specific constitutive Tissue Inhibitor of Matrix Metalloproteinase-1 (Timp1)-expression in mice under physiological and pathological conditions |
| title_exact_search | Effects of central nervous system-specific constitutive Tissue Inhibitor of Matrix Metalloproteinase-1 (Timp1)-expression in mice under physiological and pathological conditions |
| title_full | Effects of central nervous system-specific constitutive Tissue Inhibitor of Matrix Metalloproteinase-1 (Timp1)-expression in mice under physiological and pathological conditions submitted by Gioia Althoff Ruhlmann |
| title_fullStr | Effects of central nervous system-specific constitutive Tissue Inhibitor of Matrix Metalloproteinase-1 (Timp1)-expression in mice under physiological and pathological conditions submitted by Gioia Althoff Ruhlmann |
| title_full_unstemmed | Effects of central nervous system-specific constitutive Tissue Inhibitor of Matrix Metalloproteinase-1 (Timp1)-expression in mice under physiological and pathological conditions submitted by Gioia Althoff Ruhlmann |
| title_short | Effects of central nervous system-specific constitutive Tissue Inhibitor of Matrix Metalloproteinase-1 (Timp1)-expression in mice under physiological and pathological conditions |
| title_sort | effects of central nervous system specific constitutive tissue inhibitor of matrix metalloproteinase 1 timp1 expression in mice under physiological and pathological conditions |
| topic_facet | Hochschulschrift |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027501328&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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