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Aging-associated changes in B-lympho...

Guerrettaz, Lisa Michelle.

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Aging-associated changes in B-lymphopoiesis.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Aging-associated changes in B-lymphopoiesis./
Author:	Guerrettaz, Lisa Michelle.
Description:	155 p.
Notes:	Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0209.
Contained By:	Dissertation Abstracts International71-01B.
Subject:	Health Sciences, Aging. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3395916
ISBN:	9781109588378

Aging-associated changes in B-lymphopoiesis.
Guerrettaz, Lisa Michelle.

Aging-associated changes in B-lymphopoiesis. - 155 p.

Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0209.

Thesis (Ph.D.)--University of Colorado Health Sciences Center, 2009.

Aging is associated with a diminished ability to mount protective primary humoral immune responses to newly encountered pathogens. Immunologic aging develops asynchronously, in both humans and mice, with immune function of some individuals declining more rapidly than others. The effects of aging on the adaptive immune system are widespread and result from a decline in hematopoietic stem cell (HSC) function. Although studies in our laboratory and others have revealed that aged mice display an increased frequency of HSC, these cells have reduced capacity to commit to the B-lineage both in vivo and in vitro. The central hypothesis for this thesis is that immunologic aging in the B cell compartment is initiated by stem cell intrinsic changes. Thus, the objectives for this project were to (i) investigate whether B cell repertoire changes were a result of acquired hematopoietic stem cell defects, and (ii) evaluate changes in B cell commitment in vitro, and (ii) generate conditionally immortalized hematopoietic stem cell lines (ctLT-HSC) from young and aged animals as a tool for investigating the underlying molecular mechanism(s) in the age-associated decline in B-lymphopoiesis. Conclusions from this thesis are (i) that the reduced B-cell generative capacity of aged long-term reconstituting hematopoietic stem cells (LT-HSC) alters the antigen specificities in the peripheral B cell repertoire, (ii) ectopic expression of a B lineage commitment factor, Early B cell Factor (EBF), is insufficient to restore B cell differentiative capacity of aged HSC, and (iii) that epigenetic changes in aged HSC likely limits their ability to give rise to B cells. Furthermore, an epigenetic basis is suggested by changes in expression of genes involved in DNA repair, chromatin remodeling and silencing in aged ctLT-HSC. Taken together, this work indicates that the defects associated with aging of the immune system are widespread and extend from cell intrinsic changes in the hematopoietic stem cells.

ISBN: 9781109588378Subjects--Topical Terms:

1669845
Health Sciences, Aging.

Aging-associated changes in B-lymphopoiesis.
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100 1 $a Guerrettaz, Lisa Michelle. $3 1682761
245 1 0 $a Aging-associated changes in B-lymphopoiesis.
300 $a 155 p.
500 $a Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0209.
500 $a Adviser: John C. Cambier.
502 $a Thesis (Ph.D.)--University of Colorado Health Sciences Center, 2009.
520 $a Aging is associated with a diminished ability to mount protective primary humoral immune responses to newly encountered pathogens. Immunologic aging develops asynchronously, in both humans and mice, with immune function of some individuals declining more rapidly than others. The effects of aging on the adaptive immune system are widespread and result from a decline in hematopoietic stem cell (HSC) function. Although studies in our laboratory and others have revealed that aged mice display an increased frequency of HSC, these cells have reduced capacity to commit to the B-lineage both in vivo and in vitro. The central hypothesis for this thesis is that immunologic aging in the B cell compartment is initiated by stem cell intrinsic changes. Thus, the objectives for this project were to (i) investigate whether B cell repertoire changes were a result of acquired hematopoietic stem cell defects, and (ii) evaluate changes in B cell commitment in vitro, and (ii) generate conditionally immortalized hematopoietic stem cell lines (ctLT-HSC) from young and aged animals as a tool for investigating the underlying molecular mechanism(s) in the age-associated decline in B-lymphopoiesis. Conclusions from this thesis are (i) that the reduced B-cell generative capacity of aged long-term reconstituting hematopoietic stem cells (LT-HSC) alters the antigen specificities in the peripheral B cell repertoire, (ii) ectopic expression of a B lineage commitment factor, Early B cell Factor (EBF), is insufficient to restore B cell differentiative capacity of aged HSC, and (iii) that epigenetic changes in aged HSC likely limits their ability to give rise to B cells. Furthermore, an epigenetic basis is suggested by changes in expression of genes involved in DNA repair, chromatin remodeling and silencing in aged ctLT-HSC. Taken together, this work indicates that the defects associated with aging of the immune system are widespread and extend from cell intrinsic changes in the hematopoietic stem cells.
590 $a School code: 0831.
650 4 $a Health Sciences, Aging. $3 1669845
650 4 $a Health Sciences, Immunology. $3 1017716
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