The role of alphavbeta3 and alphavbeta6 integrins in liver fibrosis:
Gespeichert in:
| Beteilige Person: | |
|---|---|
| Format: | Buch |
| Sprache: | Englisch Deutsch |
| Veröffentlicht: |
2005
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| Schlagwörter: | |
| Links: | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=013170145&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| Beschreibung: | Erlangen-Nürnberg, Univ., Diss., 2005. - Enth. dt. Zsfassung |
| Umfang: | 123 S. Ill., graph. Darst. |
Internformat
MARC
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| 245 | 1 | 0 | |a The role of alphavbeta3 and alphavbeta6 integrins in liver fibrosis |c von Eleonora Patsenker |
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Datensatz im Suchindex
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| adam_text | TABLE OF CONTENTS
TABLE OF CONTENTS
ABBREVIATIONS . „ ..„ 5
LIST OF FIGURES... . .................. ........... . .......... ™...... 7
LIST OF TABLES 9
1. LITERATURE OVERVIEW AND INTRODUCTION 10
1.1. Epidemiology and social impact of chronic liver disease 10
1.2. Mechanisms of hepatic fibrogenesis 11
1.2.1. Extracellular matrix composition in health and in chronic liver diseases 13
1.2.2. The hepatic stellate cell as a major effector cell in liverfibrosis 14
1.2.3. Experimental models of liver fibrosis 16
1.2.3.1. In vitro hepatic fibrosis models 16
1.2.3.2. In vivo hepatic fibrosis models 16
13. INTEGRINS AS CELL CELL AND CELL ECM INTERACTIONS MOLECULES 17
1.3.1. as integrin family 19
1.3.1.1. ccvf)3 integrin 19
13.1.2. avp6 integrin 21
1.3.2. Integrin signaling 23
1.3.2.1. Focal adhesion kinase 24
2. RESULTS AND DISCUSSION I: POTENTIAL INVOLVEMENT OF avp3
INTEGRIN IN LIVER FIBROSIS 27
2.1. av|33 INTEGRIN EXPRESSION IN DIFFERENT ORGANS OF HEALTHY RATS 27
2.2. (53 INTEGRIN EXPRESSION IN FRESHLY ISOLATED RAT LIVER CELLS 28
2.3. j}3 INTEGRIN EXPRESSION IS UPREGULATED DURING ACTIVATION OF HEPATIC
STELLATE CELLS 29
2.4. av|$3 INTEGRIN EXPRESSION IN RAT LIVER FIBROSIS IN VIVO 31
2.4.1. Fibrosis and fibrogenic mRNA expression in livers of rats after BDL and TAA
treatment 31
2.4.2. Histology ofBDL and TAA induced rat liver fibrosis 33
2.4.3. Oto/33 integrin expression in experimental liver fibrosis 34
2.4.4. f$3 integrin mRNA expression is associated with fibrosis progression 36
2.5. PDGF BB and PDGFR J5 expresssion in liver fibrosis 37
2.5.1. PDGF BB and PDGFR Pexpression in freshly isolated liver cells 38
2.5.2. PDGF BB and PDGFR P expression during activation ofHSC in vitro 40
2.5.3. PDGF BB and PDGFR P mRNA expression in rats with secondary biliary
fibrosis 42
2.6. Interactions of PDGF BB with av[J3 integrin 44
2.6.1. PDGF BB upregulates ov/QS integrin mRNA expression in HSC 44
TABLE OF CONTENTS |
2.6.2. PDGF BB induces Oe/p3 integrin phosphorylation in hepatic stellate cells 45
2.7. Summary of part I .... 46
3. RESULTS AND DISCUSSION II: INFLUENCE OF aV03 INTEGRIN
INHIBITION ON LIVER FIBROGENESIS . „ 47
3.1. OVJJ3 INTEGRIN INHIBITION: IN VITRO STUDIES „ 47
3.1.1. avfB integrin inhibition blocks PDGF BB induced migration ofHSC 48
3.1.2. The effect ofa»f inhibition on HSC migration stimulated by fetal calf serum.. 50
3.1.3. Effect of 00/03 inhibition on HSC viability and proliferation 5/
3.1.4. FAK, paxillin andp38 mediate migratqry signals induced by ov/33 in hepatic
stellate cells 53
3.1.5. The effect of the anfi3 integrin inhibitor EMD409915 onfibrogenic gene
expression in activated rat HSC 56
3.2. avp3 integrin inhibition: in vivo study 60
3.2.1. Weights of normal and bile duct ligated rats with or without av/33 antagonist
treatment 60
3.2.2. Effect ofe» p3 antagonism on the development of biliary Jibrosis in rats 61
3.2.3. Fibrosis associated mRNA expression in BDLflbrotic rat livers with and without
treatment with the av/93 integrin antagonist 63
3.2.4. Histology of livers from bile duct ligated animals with/without ov/B inhibitor
treatment 64
3.3. Summary of part II................... 66
4. RESULTS AND DISCUSSION III: INFLUENCE OF aVP6 INTEGRIN
INHIBITION ON LIVER FIBROGENESIS 67
4.1. OV|J6 INTEGRIN EXPRESSION IN EXPERIMENTAL LIVER FIBROSIS INDUCED BY BILE
DUCT LIGATION AND THIOACETAMIDE 67
4.2. Inhibition of av(56 integrin in vivo by the nonpeptide antagonist
EMD527040 69
4.2.1. Effect of n 06 integrin inhibition on rat secondary biliary fibrosis 69
4.2.2. Pro and antifibrogenic transcript levels in rats with secondary biliary fibrosis
with/without anJ36 antagonist treatment 72
4.2.3. Liver histology of livers of rats with secondary biliary fibrosis treated with/without
the o$/fS6 integrin inhibitor ?4
4.3. Summary of part HI 76
5. RESULTS AND DISCUSSION IV: TRANSLATION OF EXPERIMENTAL
RESULTS INTO CLINICAL APPLICATION: STUDIES ON THE ASSOCIATION OF
aVp6 INTEGRIN EXPRESSION AND FIBROSIS PROGRESSION 78
5.1. av|$6 EXPRESSION IN LIVERS OF PATIENTS WITH CHRONIC HEPATITIS C 78
5.2. Pattern of avf)6 integrin expression in liver explants of patients with
par 79
TABLE OF CONTENTS
5.3. Summary of part IV ..,......................................._.........„........,.......„...................... 80
6. MATERIALS AND METHODS.....................«...«..«...._.»..™.......«..._........................ 81
6.1. COMPANIES.............. .................. .. .... ............ ........... ..... 81
6.2. EQUIPMENT AND MATERIALS 82
6.2.1. Cell culture. 82
6.2.2. Celt proliferation 82
6.2.3. Protein extraction 83
6.2.4. SDS polyacrylamide gel electrophoresis 83
6.2.5. Western Blot. 83
6.2.6. RNA extraction 84
6.2.7. Reverse transcription of RNA 85
6.2.8. Light Cycler PCR 85
63. List of buffers and solutions 86
6.4. METHODS 90
6.4.1. Cell culture 90
6.4.2. Cultivation of cell lines 90
6.4.3. Cell culture experiments 90
6.4.4. flv/33 and av/JS inlegrin inhibitors 91
6.4.5. Measurement ofDNA synthesis and cell proliferation 93
6.4.5.1. 5 Bromo 2 Deoxy uridine proliferation assay...... 93
6.4.5.2. Cell counting 93
6.4.6. Cell migration 94
6.4.7. Cell viability 95
6.4.8. Rat liver cell isolation and culture 95
6.4.8.1. Rat HSC isolation and culture 95
6.4.8.2. Rat Kupffer cell isolation and culture 96
6.4.8.3. Rat hepatocyte isolation and culture 96
6.4.9. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western Blot.... 97
6.4.9.1. Protein extraction from cell culture 97
6.4.9.2. SDS polyacrylamide gel electrophoresis and Western Blotting 97
6.4.10. Animal experiments 98
6.4.10.1. BDL model of secondary biliary fibrosis in rat 98
6.4.10.2. TAA induced liver fibrosis in rats 99
6.4.11. Patients 99
6.4.11.1. Stage and grade of fibrosis 100
6.4.12. RNA extraction 100
6.4.12.1. Isolation of RNA from cell culture 100
6.4.12.2. Isolation of RNA from rat tissues 101
6.4.12.3. Isolation of RNA from biopsies of Hepatitis C patients and from human
liver explants 101
6.4.12.4. Measurement of RNA concentration by DV spectroscopy 101
1
TABLE OF CONTENTS
6.4.12.5. Determination of RNA integrity on an agarose gel . 101
6.4.13. Reverse transcription ofmRNA 102
6.4.14. Measurement of gene expression by real time PCR 102
6.4.14.1. TaqMan PCR ..... „ ................... ... . ..... 102
6.4.14.2. SVBR Green PCR........ ................ . . 103
6.4.14 J. Design of Primers and Probes .................................................. .... 104
6.4.14.4. PCR procedure............ 105
154.IS. Hydroxyproline determination 106
6.4.16. Histologicalassessment* 106
6.4.17. Immunohistology* 106
6.4.18. Serum marker determinations* 107
6.5. Statistics 107
7. SUMMARY . ... „„. „...„ 108
8. REFERENCES .... ....„ 110
DEUTSCHE ZUSAMMENFASSUNG.... _ 122
CURRICULUM VITAE .„.„ . 124
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| genre_facet | Hochschulschrift |
| id | DE-604.BV019845318 |
| illustrated | Illustrated |
| indexdate | 2024-12-20T12:07:07Z |
| institution | BVB |
| language | English German |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-013170145 |
| oclc_num | 162299791 |
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| physical | 123 S. Ill., graph. Darst. |
| publishDate | 2005 |
| publishDateSearch | 2005 |
| publishDateSort | 2005 |
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| spellingShingle | Patsenker, Eleonora 1979- The role of alphavbeta3 and alphavbeta6 integrins in liver fibrosis Integrine (DE-588)4278201-6 gnd Leberfibrose (DE-588)4167063-2 gnd |
| subject_GND | (DE-588)4278201-6 (DE-588)4167063-2 (DE-588)4113937-9 |
| title | The role of alphavbeta3 and alphavbeta6 integrins in liver fibrosis |
| title_auth | The role of alphavbeta3 and alphavbeta6 integrins in liver fibrosis |
| title_exact_search | The role of alphavbeta3 and alphavbeta6 integrins in liver fibrosis |
| title_full | The role of alphavbeta3 and alphavbeta6 integrins in liver fibrosis von Eleonora Patsenker |
| title_fullStr | The role of alphavbeta3 and alphavbeta6 integrins in liver fibrosis von Eleonora Patsenker |
| title_full_unstemmed | The role of alphavbeta3 and alphavbeta6 integrins in liver fibrosis von Eleonora Patsenker |
| title_short | The role of alphavbeta3 and alphavbeta6 integrins in liver fibrosis |
| title_sort | the role of alphavbeta3 and alphavbeta6 integrins in liver fibrosis |
| topic | Integrine (DE-588)4278201-6 gnd Leberfibrose (DE-588)4167063-2 gnd |
| topic_facet | Integrine Leberfibrose Hochschulschrift |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=013170145&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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