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Analysis of the regulation of murine...

Fleming, Heather Elisabeth.

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Analysis of the regulation of murine B lymphopoiesis by interleukin-7 and the pre-B cell receptor.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Analysis of the regulation of murine B lymphopoiesis by interleukin-7 and the pre-B cell receptor./
Author:	Fleming, Heather Elisabeth.
Description:	226 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-04, Section: B, page: 1674.
Contained By:	Dissertation Abstracts International64-04B.
Subject:	Health Sciences, Immunology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=NQ78382
ISBN:	0612783820

Analysis of the regulation of murine B lymphopoiesis by interleukin-7 and the pre-B cell receptor.
Fleming, Heather Elisabeth.

Analysis of the regulation of murine B lymphopoiesis by interleukin-7 and the pre-B cell receptor. - 226 p.

Source: Dissertation Abstracts International, Volume: 64-04, Section: B, page: 1674.

Thesis (Ph.D.)--University of Toronto (Canada), 2003.

Generation of the B lymphocyte lineage involves the development of early non-committed hematopoietic stem cells to mature, Ig-producing B cells. Cell-intrinsic regulatory signals combine with signals provided by the surrounding microenvironment to mediate selection checkpoints throughout the developmental process. In this thesis I examine the roles played by the pre-B cell receptor and the interleukin-7 (IL-7) receptor during a major developmental checkpoint. The transition from the pro-B to pre-B cell stage requires the formation of the pre-B cell receptor, and the signaling complexes that arise following its membrane insertion. Prior to the acquisition of the pre-B cell receptor, B cell precursors require exposure to IL-7, a growth factor produced by surrounding stromal cells. I demonstrate a connection between these two intrinsic and extrinsic signals: in the presence of the pre-B cell receptor, pre-B cells experience a reduced threshold for proliferation in response to IL-7. I establish that a signal transmitted by the pre-B cell receptor complex is sufficient to allow proliferation in response to low concentrations of IL-7. Further experiments indicate that activation of the ERK/MAP kinase pathway occurs in response to combined stimulation of the pre-B cell receptor and the IL-7 receptor, and that cells expressing the pre-B cell receptor exhibit increased levels of activated ERK even in the absence of receptor cross-linking. I propose a model for the ERK-dependent selection of pre-B cells in the presence of low concentrations of IL-7. Experimental results reveal that ERK phosphorylation is pivotal in the induction of proliferation, but not maturation or survival of cells undergoing the pro-B to pre-B transition, providing support for my hypothesis. A similar requirement for protein kinase A activity is also indicated. In summary, pre-B cells experience a pre-B cell receptor-dependent growth advantage over more immature cells in an environment that provides limited amounts of interleukin-7, a situation that may exist in the murine bone marrow. The data presented in this thesis constitute a model for the specific selection of pre-B cells that have completed a crucial developmental task, and highlight the regulatory role played by the environmental context in which cells mature.

ISBN: 0612783820Subjects--Topical Terms:

1017716
Health Sciences, Immunology.

Analysis of the regulation of murine B lymphopoiesis by interleukin-7 and the pre-B cell receptor.
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245 1 0 $a Analysis of the regulation of murine B lymphopoiesis by interleukin-7 and the pre-B cell receptor.
300 $a 226 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-04, Section: B, page: 1674.
500 $a Adviser: Christopher J. Paige.
502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2003.
520 $a Generation of the B lymphocyte lineage involves the development of early non-committed hematopoietic stem cells to mature, Ig-producing B cells. Cell-intrinsic regulatory signals combine with signals provided by the surrounding microenvironment to mediate selection checkpoints throughout the developmental process. In this thesis I examine the roles played by the pre-B cell receptor and the interleukin-7 (IL-7) receptor during a major developmental checkpoint. The transition from the pro-B to pre-B cell stage requires the formation of the pre-B cell receptor, and the signaling complexes that arise following its membrane insertion. Prior to the acquisition of the pre-B cell receptor, B cell precursors require exposure to IL-7, a growth factor produced by surrounding stromal cells. I demonstrate a connection between these two intrinsic and extrinsic signals: in the presence of the pre-B cell receptor, pre-B cells experience a reduced threshold for proliferation in response to IL-7. I establish that a signal transmitted by the pre-B cell receptor complex is sufficient to allow proliferation in response to low concentrations of IL-7. Further experiments indicate that activation of the ERK/MAP kinase pathway occurs in response to combined stimulation of the pre-B cell receptor and the IL-7 receptor, and that cells expressing the pre-B cell receptor exhibit increased levels of activated ERK even in the absence of receptor cross-linking. I propose a model for the ERK-dependent selection of pre-B cells in the presence of low concentrations of IL-7. Experimental results reveal that ERK phosphorylation is pivotal in the induction of proliferation, but not maturation or survival of cells undergoing the pro-B to pre-B transition, providing support for my hypothesis. A similar requirement for protein kinase A activity is also indicated. In summary, pre-B cells experience a pre-B cell receptor-dependent growth advantage over more immature cells in an environment that provides limited amounts of interleukin-7, a situation that may exist in the murine bone marrow. The data presented in this thesis constitute a model for the specific selection of pre-B cells that have completed a crucial developmental task, and highlight the regulatory role played by the environmental context in which cells mature.
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