IEC-specific insulin resistance impairs gut barrier function and promotes colitis-associated cancer
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| Sprache: | English |
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2018
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| 100 | 1 | |a Ostermann, Anna Lena |d 1988- |e Verfasser |0 (DE-588)1151066699 |4 aut | |
| 245 | 1 | 0 | |a IEC-specific insulin resistance impairs gut barrier function and promotes colitis-associated cancer |c vorgelegt von Anna Lena Ostermann |
| 264 | 1 | |a Köln |c 2018 | |
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| 502 | |b Dissertation |c Universität zu Köln |d 2017 | ||
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Datensatz im Suchindex
| _version_ | 1804178646390276096 |
|---|---|
| adam_text | CONTENT
1
INTRODUCTION...............................................................................................1
1.1 COLORECTAL
CANCER.....................................................................................................1
1.1.1 PHYSIOLOGY OF COLORECTAL CANCER AND RISK
FACTORS................................................1
1.1.2 INFLAMMATION AND CR C
.....................................................................................
3
1.1.3 CHEMICAL INDUCTION OF CAC BY THE TWO-STEP AOM/DSS PROTOCOL
..................
4
1.2 THE LINK BETWEEN OBESITY AND CRC
.......................................................................
5
1.2.1 OBESITY INCREASES THE RISK FOR CRC DEVELOPMENT BY ELEVATING THE
COLONIC
INFLAMMATORY
TONE.........................................................................................................
5
1.2.2 OBESITY IS A CHRONIC INFLAMMATORY STATE ORIGINATING FROM THE WAT
..................
6
1.3 INSULIN SIGNALING PATHWAY
......................................................................................
7
1.3.1 INSULIN AND INSULIN-LIKE GROWTH FACTOR 1 RECEPTORS
............................................
7
1.3.2 LIGAND BINDING TO THE IR AND IGF 1R TRIGGERS TWO DOWNSTREAM
SIGNALING
CASCADES.........................................................................................................................
9
1.3.3 INSULIN-REGULATED TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION VIA
FOXO L
.......
11
1.3.4 THE PI3K/AKT AXIS IS OVERACTIVATED IN A VARIETY OF CANCER TYPES,
INCLUDING
CRC
..........................................................................................................................13
1.3.5 OBESITY-ASSOCIATED LOW-GRADE INFLAMMATION PROMOTES INSULIN
RESISTANCE
.....
14
1.4
OBJECTIVE.................................................................................................................15
2 MATERIAL AND
METHODS............................................................................16
2.1
MATERIALS.................................................................................................................
16
2.1.1
CONSUMABLES.....................................................................................................
16
2.1.2
KITS....................................................................................................................
18
2.2 ANIMAL
CARE...........................................................................................................
18
2.2.1 HOUSING OF
MICE...............................................................................................
18
2.2.2 INDUCTION OF COLORECTAL ADENOMA
FORMATION...................................................... 19
2.3 METABOLIC
MEASUREMENTS......................................................................................20
2.3.1 SERUM/PLASMA
COLLECTION..................................................................................
20
2.3.2 GLUCOSE TOLERANCE
TEST.......................................................................................21
2.4 ORGAN DISSECTION AND
PREPARATION........................................................................21
2.4.1 DISSECTION OF
ORGANS........................................................................................
21
2.4.2 QUANTIFICATION OF TUMOR
BURDEN........................................................................21
2.4.3 PREPARATION OF CRYO
SECTIONS.............................................................................22
2.4.4 PREPARATION OF SECTIONS FOR ELECTRON MICROSCOPY
.............................................
22
2.5 ISOLATION AND CULTIVATION OF PRIMARY
CELLS............................................................22
2.5.1 ISOLATION AND STIMULATION OF INTESTINAL EPITHELIAL
CELLS.....................................22
2.5.2 ISOLATION AND STIMULATION OF PRIMARY HEPATOCYTES
............................................
23
2.5.3 ISOLATION AND CULTIVATION OF MURINE EMBRYONIC FIBROBLASTS
..............................
25
2.6 DNA/RNA
ISOLATION...............................................................................................26
2.6.1 DNA ISOLATION FROM TAIL AND
GENOTYPING......................................................... 26
2.6.2 RNA ISOLATION FROM
TISSUE................................................................................27
2.6.3 RNA ISOLATION FROM ISOLATED AND CULTIVATED CELLS
............................................
28
2.6.4 REVERSE TRANSCRIPTION OF RNA AND QPCR ANALYSIS
..........................................
28
2.6.5 MICROARRAY
ANALYSIS..........................................................................................29
2.6.6 CHROMATIN
IMMUNOPRECIPITATION.......................................................................30
2.7 PROTEIN BIOCHEMISTRY
.
...........................................................................................
31
2.7.1 PROTEIN ISOLATION FROM MURINE
TISSUE................................................................31
2.7.2 PROTEIN ISOLATION FROM ISOLATED AND CULTIVATED
CELLS......................................... 32
2.7.3 SDS POLYACRYLAMIDE
GEL-ELECTROPHORESES.........................................................33
2.7.4 WESTERN BLOT
ANALYSIS........................................................................................33
2.7.5 INSULIN
ELISA...................................................................................................34
2.7.6 MURINE ALBUMIN
ELISA...................................................................................35
2.7.7 IL-6 AND TNFA
ELISA....................................................................................37
2.8 IMMUNOHISTOCHEMICAL/ IMMUNOFLUORESCENT STAINING AND MICROSCOPY
...........
37
2.8.1 HE
STAINING......................................................................................................
37
2.8.2 IMMUNOFLUORESCENT STAININGS
..........................................................................
38
3
RESULTS....................................................................................................
39
3.1 OBESITY INDUCES INSULIN RESISTANCE IN
IECS........................................................39
3.2 IEC-SPECIFIC IR/IGF1R DOUBLE DEFICIENCY MIMICS OBESITY-ASSOCIATED
INSULIN
RESISTANCE IN IECS BUT FAILS TO ALTER SYSTEMIC GLUCOSE METABOLISM
............................
41
3.3 GENETIC IEC-SPECIFIC IR/IGF1R DEFICIENCY ELEVATES CAC BURDEN AFTER
CHEMICAL TUMOR INDUCTION BY IMPAIRMENT OF GUT BARRIER RESTORATION
......................
44
3.4 IEC-SPECIFIC EXPRESSION OF AN INSULIN-INSENSITIVE FOXOL VARIANT
RECAPITULATES
IR/IGF1R
IEC
KO
CAC PHENOTYPE
________________________________________
49
3.4.1 IEC-SPECIFIC EXPRESSION OF NUCLEAR RETAINED FOXOL ADA VERSION
FAILS TO ALTER
SYSTEMIC GLUCOSE
METABOLISM......................................................................................
49
3.4.2 NUCLEAR RETENTION OFFOXO 1 ADA ELEVATES CAC BURDEN SIMILAR AS IN
IR/IGF 1
RIEC
_
KO
MICE...................................................................................................
51
3.4.3 ELEVATED CAC DEVELOPMENT IN FOXOL ADAIEC MICE IS ACCOMPANIED WITH
HIGHER SYSTEMIC
INFLAMMATION.....................................................................................
53
3.5 INSULIN-SIGNALING DEFICIENCY ALTERS
DSC3 EXPRESSION
..........................................
55
3.5.1 NUCLEAR RETENTION OF FOXO 1 INHIBITS
DSC3 EXPRESSION UNDER INSULIN RESISTANCE..
.........................................................................................................................
55
3.5.2 REDUCED
DSC3 EXPRESSION IMPAIRS DESTNOSOMAL ARCHITECTURE AND RESULTS IN
MISLOCALIZATION OF DESMOPLAKIN
1/2............................................................................
59
3.6 IEC-SPECIFIC DEFICENCY OF DSC3 ELEVATES CAC BURDEN AND INCREASES
SYSTEMIC
INFLAMMATION..................................................................................................................
62
3.7 A NEW GENETIC MODEL FOR CAC INDUCTION DEPENDS ON INSULIN-REGULATED
GENE
EXPRESSION VIA F OXO
L....................................................................................................
64
4
DISCUSSION.................................................................................................68
4.1 INSULIN RESISTANCE IN IECS IS INDUCED BY HFD-FEEDING AND MIMICKED BY
IR/IGF1R INACTIVATION
......................
.
..........................................................................
69
4.2 FUNCTIONAL ROLE OF IR AND IGF1R IN NORMAL COLON PHYSIOLOGY AND IN
CRC... 70
4.3 IEC-SPECIFIC INSULIN RESISTANCE IMPACTS ON CAC BURDEN DUE TO ALTERED
DSC3
EXPRESSION........................................................................................................................
71
4.3.1 CONSEQUENCES OF REDUCED
DSC3 ON TUMOR DEVELOPMENT
...................................
73
4.3.2 ELEVATED THL7 RESPONSE DRIVES CAC
DEVELOPMENT.........................................74
4.4 FOXOL - A NEWLY IDENTIFIED TRANSCRIPTION FACTOR THAT REGULATES
DSC3 EXPRESSION
.................................................................................................................................
75
4.5 CONCLUSION
..............................................................
78
5
BIBLIOGRAPHY............................................................................................
80
6
DANKSAGUNG..............................................................................................
94
7
ERKLAERUNG.................................................................................................
95
8 CURRICULUM VITAE
96
|
| any_adam_object | 1 |
| author | Ostermann, Anna Lena 1988- |
| author_GND | (DE-588)1151066699 |
| author_facet | Ostermann, Anna Lena 1988- |
| author_role | aut |
| author_sort | Ostermann, Anna Lena 1988- |
| author_variant | a l o al alo |
| building | Verbundindex |
| bvnumber | BV045053010 |
| ctrlnum | (OCoLC)1136403622 (DE-599)DNB1155027531 |
| discipline | Medizin |
| format | Thesis Book |
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| spelling | Ostermann, Anna Lena 1988- Verfasser (DE-588)1151066699 aut IEC-specific insulin resistance impairs gut barrier function and promotes colitis-associated cancer vorgelegt von Anna Lena Ostermann Köln 2018 xii, 98 Seiten Illustrationen 21 cm txt rdacontent n rdamedia nc rdacarrier Dissertation Universität zu Köln 2017 (DE-588)4113937-9 Hochschulschrift gnd-content B:DE-101 application/pdf http://d-nb.info/1155027531/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030444715&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Ostermann, Anna Lena 1988- IEC-specific insulin resistance impairs gut barrier function and promotes colitis-associated cancer |
| subject_GND | (DE-588)4113937-9 |
| title | IEC-specific insulin resistance impairs gut barrier function and promotes colitis-associated cancer |
| title_auth | IEC-specific insulin resistance impairs gut barrier function and promotes colitis-associated cancer |
| title_exact_search | IEC-specific insulin resistance impairs gut barrier function and promotes colitis-associated cancer |
| title_full | IEC-specific insulin resistance impairs gut barrier function and promotes colitis-associated cancer vorgelegt von Anna Lena Ostermann |
| title_fullStr | IEC-specific insulin resistance impairs gut barrier function and promotes colitis-associated cancer vorgelegt von Anna Lena Ostermann |
| title_full_unstemmed | IEC-specific insulin resistance impairs gut barrier function and promotes colitis-associated cancer vorgelegt von Anna Lena Ostermann |
| title_short | IEC-specific insulin resistance impairs gut barrier function and promotes colitis-associated cancer |
| title_sort | iec specific insulin resistance impairs gut barrier function and promotes colitis associated cancer |
| topic_facet | Hochschulschrift |
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