The role of pro- and anti-apoptotic proteins for homeostasis and function of mast cells:
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| Main Author: | |
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| Format: | Thesis Book |
| Language: | English German |
| Published: |
2014
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| Subjects: | |
| Online Access: | Inhaltsverzeichnis |
| Item Description: | Zsfassung in dt. und engl. Sprache |
| Physical Description: | 84 S. Ill., graph. Darst. |
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| adam_text | Titel: The role of pro- and anti-apoptotic proteins for homeostasis and function of mast cells
Autor: Förster, Anja
Jahr: 2014
Table of contents
1 Introduction......................1
1.1 Mast cells.................................................................................................................................1
1.1.1 Development of mast cells..............................................................................................1
1.1.2 Subtypes of mast cells.....................................................................................................1
1.1.3 Activation of mast cells....................................................................................................2
1.1.4 The role of mast cells in immunity and hypersensitivity..................................................3
1.1.5 Mastocytosis....................................................................................................................9
1.1.6 Mouse models of mast cell deficiency and mast cell-specific gene deletion...................6
1.2 Cell death.................................................................................................................................9
1.2.1 Apoptosis.........................................................................................................................9
1.2.2 Necrosis.........................................................................................................................11
1.2.3 Other types of cell death................................................................................................12
1.2.4 Bcl-2 family proteins......................................................................................................12
1.2.5 Mcl-1..............................................................................................................................15
1.2.6 Bcl-xL.............................................................................................................................16
1.2.7 TRAIL-Rs.......................................................................................................................17
1.3 Regulation of cell death in mast cells....................................................................................19
2 Objectives........................................................................................................21
3 Material and Methods......................................................................................22
3.1 Chemicals..............................................................................................................................22
3.2 Buffers...................................................................................................................................22
3.3 Mice.......................................................................................................................................22
3.4 Genotyping............................................................................................................................23
3.4.1 Isolation of genomic tail DNA........................................................................................23
3.4.2 PCR...............................................................................................................................23
3.5 Histology................................................................................................................................24
3.6 Passive systemic anaphylaxis...............................................................................................25
3.7 Cell culture.............................................................................................................................25
3.7.1 WEHI-3B........................................................................................................................25
3.7.2 CHO...........................................................................................................................25
3.7.3 BMMC..................................................................................................................26
3.7.4 PCMC......................................................................................................................................................................................................26
3.7.5 HMC-1 ..........................................................................................................................................................................................26
3.7.6 TF1 ...............................................26
3.8 Flow cytometry.......................................................................................................................27
3.8.1 Analysis of myeloid and lymphoid cells in spleen and peritoneal cavity.......................27
3.8.2 Evaluation of viability and apoptosis by flow cytometry.................................................28
3.8.3 Surface expression of TRAIL-Rs...................................................................................28
3.9 Western blotting.....................................................................................................................29
3.10 Apoptosis of BMMC in response to growth factor deprivation..............................................29
3.11 Viability and apoptosis upon incubation with ActD and etoposide........................................30
3.12 Viability and apoptosis upon incubation with TRAIL..............................................................30
3.13 RT-PCR to detect TRAIL-R transcripts..................................................................................30
3.14 Growth rate of BMMC............................................................................................................31
3.15 ß-Hexosaminidase assay......................................................................................................31
3.16 Statistical analysis.................................................................................................................31
4 Results.............................................................................................................32
4.1 Generation of mast cell-specific Mcl-1, Bcl-x and TRAIL-R knockout mice..........................32
4.2 Mcl-1 serves as central regulator of mast cell homeostasis..................................................34
4.2.1 Mast cell-specific deletion of Mcl-1 results in mast cell deficiency................................34
4.2.2 Numbers of myeloid and lymphoid cells in spleen and peritoneal cavity are not affected
by the Mcpf5Cre-mediated deletion of Mcl-1.................................................................38
4.2.3 Mcpt5Cre/Mcl-1m mice are protected from IgE-mediated passive systemic anaphylaxis
.......................................................................................................................................39
4.3 Bcl-xL participates in the regulation of mast cell survival......................................................41
4.3.1 Mast cell numbers are partially reduced in Mcpt5Cre/Bcl-x mice..............................41
4.3.2 IgE-mediated passive systemic anaphylaxis is not affected in Mcpt5Cre/Bcl-xm mice 43
4.3.3 Bcl-x-deficient mast cells develop in vitro......................................................................43
4.3.4 Mx1Cre/Bcl-x BMMC show absence of Bcl-xL and increased levels of Mcl-1...........45
4.3.5 Deletion of Bcl-x has no impact on apoptosis in response to growth factor deprivations
4.3.6 Apoptosis in response to antineoplastic drugs is increased in Bc/-x-deficient mast cells.
.......................................................................................................................................47
4.3.7 TRAIL-induced apoptosis is increased in Bcl-x-deficient mast cells.............................50
4.4 The function of TRAIL-R is regulated by KIT activation........................................................51
4.4.1 Deletion of TRAIL-R has no impact on turnover of murine mast cells..........................51
4.4.2 IgE-mediated passive systemic anaphylaxis is extended in Mcpt5Cre/TRAIL-Rmmice..
.......................................................................................................................................53
4.4.3 Deletion of TRAIL-R is highly efficient in PCMC and BMMC cultured from TRAIL-Rf°
mice...............................................................................................................................53
4.4.4 Wild type PCMC and BMMC fail to undergo TRAIL-mediated cell death.....................55
4.4.5 Turnover and growth factor deprivation-induced apoptosis are not affected in TRAIL-Rko
BMMC............................................................................................................................55
4.4.6 Deletion of TRAIL-R fails to affect degranulation of mast cells.....................................56
4.4.7 SCF-induced KIT activation enhances the susceptibility towards TRAIL-mediated cell
death..............................................................................................................................57
4.4.8 The extent of activating KIT mutations correlates with the expression of TRAIL-Rs and
the sensitivity towards TRAIL-induced cell death..........................................................58
5 Discussion.......................................................................................................63
5.1 Generation of a new mouse model of mast cell deficiency...................................................63
5.1.1 Other mouse models of mast cell deficiency.................................................................64
5.1.2 Efficiency of mast cell ablation......................................................................................65
5.1.3 Future investigations......................................................................................................66
5.2 Involvement of Bcl-xL in the homeostasis of mast cells........................................................68
5.2.1 Bcl-xL partially ensures the survival of mast cells in vivo..............................................68
5.2.2 Bcl-xL is dispensable for development of mast cells in vitro.........................................69
5.2.3 Absence of Bcl-xL results in upregulation of Mcl-1.......................................................69
5.3 Activation of KIT modulates the function of TRAIL-R in mast cells.......................................72
5.3.1 Discrepancies in TRAIL-R function between human and murine mast cells.................72
5.3.2 Involvement of death receptors in the homeostasis and function of murine mast cells 73
5.3.3 Clinical implication of TRAIL-R regulation.....................................................................73
6 References.......................................................................................................75
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| any_adam_object | 1 |
| author | Förster, Anja |
| author_GND | (DE-588)1064623980 |
| author_facet | Förster, Anja |
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| dewey-full | 610 |
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| dewey-ones | 610 - Medicine and health |
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| dewey-sort | 3610 |
| dewey-tens | 610 - Medicine and health |
| discipline | Medizin |
| format | Thesis Book |
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| spelling | Förster, Anja Verfasser (DE-588)1064623980 aut The role of pro- and anti-apoptotic proteins for homeostasis and function of mast cells vorgelegt von Anja Förster 2014 84 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Zsfassung in dt. und engl. Sprache Köln, Univ., Diss., 2014 Mastzelle (DE-588)4194827-0 gnd rswk-swf Homöostase (DE-588)4160575-5 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Homöostase (DE-588)4160575-5 s Mastzelle (DE-588)4194827-0 s DE-188 HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027923016&sequence=000004&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Förster, Anja The role of pro- and anti-apoptotic proteins for homeostasis and function of mast cells Mastzelle (DE-588)4194827-0 gnd Homöostase (DE-588)4160575-5 gnd |
| subject_GND | (DE-588)4194827-0 (DE-588)4160575-5 (DE-588)4113937-9 |
| title | The role of pro- and anti-apoptotic proteins for homeostasis and function of mast cells |
| title_auth | The role of pro- and anti-apoptotic proteins for homeostasis and function of mast cells |
| title_exact_search | The role of pro- and anti-apoptotic proteins for homeostasis and function of mast cells |
| title_full | The role of pro- and anti-apoptotic proteins for homeostasis and function of mast cells vorgelegt von Anja Förster |
| title_fullStr | The role of pro- and anti-apoptotic proteins for homeostasis and function of mast cells vorgelegt von Anja Förster |
| title_full_unstemmed | The role of pro- and anti-apoptotic proteins for homeostasis and function of mast cells vorgelegt von Anja Förster |
| title_short | The role of pro- and anti-apoptotic proteins for homeostasis and function of mast cells |
| title_sort | the role of pro and anti apoptotic proteins for homeostasis and function of mast cells |
| topic | Mastzelle (DE-588)4194827-0 gnd Homöostase (DE-588)4160575-5 gnd |
| topic_facet | Mastzelle Homöostase Hochschulschrift |
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