Studies on Molecular Genetics of B cell Development
(2004)- Abstract
- The development of immature progenitor cells into highly differentiated effector cells is a process central in modern medicine with applications in the fields of cell therapy as well as oncology. This thesis is focused on the molecular mechanisms that control the development of B lymphocytes. This is a complex and tightly regulated process involving several stages proceeding from stem cells to antibody-secreting plasma cells. B cell development is regulated through the action of transcription factors and cytokines that act in concert to control the pathway. Some of the work presented herein utilized broad RNA expression analysis of several mouse B cell-lines representing different stages of B cell development, to identify genes with... (More)
- The development of immature progenitor cells into highly differentiated effector cells is a process central in modern medicine with applications in the fields of cell therapy as well as oncology. This thesis is focused on the molecular mechanisms that control the development of B lymphocytes. This is a complex and tightly regulated process involving several stages proceeding from stem cells to antibody-secreting plasma cells. B cell development is regulated through the action of transcription factors and cytokines that act in concert to control the pathway. Some of the work presented herein utilized broad RNA expression analysis of several mouse B cell-lines representing different stages of B cell development, to identify genes with restricted expression pattern in B cell development. It also revealed that B cell-lines arrested at a certain stage of B cell development display high similarity in overall expression pattern allowing the usage of this experimental system to define genetically linked genes. Based on these experiments, mathematical methods to analyze the linkage of genes in a complex data set were developed. The efficiency of this approach was shown by the verified identification of genetic targets for the transcription factor EBF. The integration of intracellular and extracellular signals was investigated using the Ialpha promoter, involved in class switch recombination to IgA, to investigate how sterile transcription from this promoter is stimulated by TGFbeta1. This revealed a functional synergy between the intracellular mediators of TGFbeta signaling, SMAD proteins, and the transcription factor AML1. This study provides explanations for how extracellular signals can be integrated into the transcriptional regulatory pathways in the cell in terminal B cell development. (Less)
- Abstract (Swedish)
- Popular Abstract in Swedish
Trots att vår kropp är uppbygd av ett stort antal celler med så olika funktioner som att skapa ben och försvara oss mot infektioner, innehåller alla celler samma genetiska information. Denna information är lagrad i cellens chromosomer i form av DNA och cell specifica egenskaper uppstår då olika delar av kromosomernas information används i olika vävnader. Således, måste vi för att förstå hur en cell med speciella funktioner genereras, lära oss hur specifika delar av den genetiska infomationen kan väljas ut i olika typer av celler. Denna förståelse är av central betydelse för att kunna utveckla cell baserade terapier med omogna celler (stamceller) men även för att kunna förbättra behandlinen av... (More) - Popular Abstract in Swedish
Trots att vår kropp är uppbygd av ett stort antal celler med så olika funktioner som att skapa ben och försvara oss mot infektioner, innehåller alla celler samma genetiska information. Denna information är lagrad i cellens chromosomer i form av DNA och cell specifica egenskaper uppstår då olika delar av kromosomernas information används i olika vävnader. Således, måste vi för att förstå hur en cell med speciella funktioner genereras, lära oss hur specifika delar av den genetiska infomationen kan väljas ut i olika typer av celler. Denna förståelse är av central betydelse för att kunna utveckla cell baserade terapier med omogna celler (stamceller) men även för att kunna förbättra behandlinen av cancer då en tumör cell ofta utnyttjar “fel” delar av det genetisk materialet.
I denna avhandling studeras de mekanismer som styr utvecklingen av antikropps producerande vita blod kroppar (B- lymfocyter) från omogna blod stamceller i benmärgen. För dessa studier änvänds en kombination av molekylärbiologi och matematiska metoder för att visa hur vissa speciella proteiner (transkriptions faktorer) som reglerar användandet av DNAt (transkription), arbetar för att skapa genetiska nätvärk och på så sätt samordnar användandet av den genetiska informationen trots att den är spridd på kromosomerna. En annan aspekt som studerats är hur dessa transkriptions faktorer samarbetar för att etablera de speciella mönster av DNA användning som är karakteristiska för B-lymfocytens olika utvecklings stadier.
Dessa studier har ökat vår kunskap om specifika transkriptions faktorer med central roll för B-lymfocytens utveckling men även försett oss med verktyg som kan användas vid studier av andra celler utvekling, specialisering och transformation. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/467056
- author
- Tsapogas, Panagiotis LU
- supervisor
- opponent
-
- Dr Steffen Junker, Steffen Junker, Institut for Human Genetik, Aarhus Universitet, Denmark
- organization
- publishing date
- 2004
- type
- Thesis
- publication status
- published
- subject
- keywords
- immunoglobulin, gene expression, B cell, EBF, class switching, TGF-beta, Immunology, transplantation, serologi, Immunologi, serology
- pages
- 138 pages
- publisher
- Panagiotis Tsapogas, Section for Immunology, BMC I-13, S-221 84, Lund,
- defense location
- Saturday, 12th of June 2004, 9.00 am, Segerfalksalen, Wallenberg Neurocentrum, Sölvegatan 17
- defense date
- 2004-06-12 09:00:00
- ISBN
- 91-628-6125-5
- language
- English
- LU publication?
- yes
- id
- 30d3b1b3-3ebf-4ebf-a356-ccb43b1a7069 (old id 467056)
- date added to LUP
- 2016-04-04 11:13:52
- date last changed
- 2018-11-21 21:03:30
@phdthesis{30d3b1b3-3ebf-4ebf-a356-ccb43b1a7069,
abstract = {{The development of immature progenitor cells into highly differentiated effector cells is a process central in modern medicine with applications in the fields of cell therapy as well as oncology. This thesis is focused on the molecular mechanisms that control the development of B lymphocytes. This is a complex and tightly regulated process involving several stages proceeding from stem cells to antibody-secreting plasma cells. B cell development is regulated through the action of transcription factors and cytokines that act in concert to control the pathway. Some of the work presented herein utilized broad RNA expression analysis of several mouse B cell-lines representing different stages of B cell development, to identify genes with restricted expression pattern in B cell development. It also revealed that B cell-lines arrested at a certain stage of B cell development display high similarity in overall expression pattern allowing the usage of this experimental system to define genetically linked genes. Based on these experiments, mathematical methods to analyze the linkage of genes in a complex data set were developed. The efficiency of this approach was shown by the verified identification of genetic targets for the transcription factor EBF. The integration of intracellular and extracellular signals was investigated using the Ialpha promoter, involved in class switch recombination to IgA, to investigate how sterile transcription from this promoter is stimulated by TGFbeta1. This revealed a functional synergy between the intracellular mediators of TGFbeta signaling, SMAD proteins, and the transcription factor AML1. This study provides explanations for how extracellular signals can be integrated into the transcriptional regulatory pathways in the cell in terminal B cell development.}},
author = {{Tsapogas, Panagiotis}},
isbn = {{91-628-6125-5}},
keywords = {{immunoglobulin; gene expression; B cell; EBF; class switching; TGF-beta; Immunology; transplantation; serologi; Immunologi; serology}},
language = {{eng}},
publisher = {{Panagiotis Tsapogas, Section for Immunology, BMC I-13, S-221 84, Lund,}},
school = {{Lund University}},
title = {{Studies on Molecular Genetics of B cell Development}},
year = {{2004}},
}