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dc.contributor.advisorDaniels, Mark A.eng
dc.contributor.authorOlson, William Josepheng
dc.date.issued2011eng
dc.date.submitted2011 Falleng
dc.descriptionTitle from PDF of title page (University of Missouri--Columbia, viewed on June 11, 2012).eng
dc.descriptionThe entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.eng
dc.descriptionThesis advisor: Dr. Mark A. Danielseng
dc.descriptionIncludes bibliographical references.eng
dc.descriptionM.S. University of Missouri-Columbia 2011.eng
dc.descriptionDissertations, Academic -- University of Missouri--Columbia -- microbiology (Medicine).eng
dc.description"December, 2011"eng
dc.description.abstractThymocytes undergo a process of development that serves to favor the differentiation of T-cells bearing self-MHC (major histo-compatibility complex) restricted T-cell receptors (TCR). Signaling through the TCR is crucial for the development from double positive (CD4+CD8+, referred to as DP) thymocytes into mature T-cells. Strong or no affinity interaction between MHC and the TCR leads to apoptosis and is considered as negative selection or death by neglect respectively. A weak to moderate affinity signal initiates differentiation of DP cells into single positive cells (positive for either CD4 or CD8, SP) termed positive selection. The importance of several pathways for either negative or positive selection has been described. However, the molecular events that allow the differentiation of a positive versus negative selecting signal are unclear because, engagement of the TCR leads to activation of all pathways known to play a role in selection. It has been suggested that differential localization of the extra cellular regulated kinase 1/2 (ERK) pathway plays a key role in selection. Here we examine the localization of ERK activation in thymic selection by the manipulating calcium levels leading alterations in RasGRP location and through a Raf construct targeted to either the plasma membrane or the golgi. We also examine differences in β-catenin expression and its role in the expression of Bcl-XL, a pro-survival molecule critical for survival at the DP stage. We find that activation of the ERK pathway from the plasma membrane converts positive selection to negative selection, while the activation of ERK from the golgi upon stimulation by a negative selector causes a deviation of these cells from apoptosis into the CD8αα+ lineage. In addition we show that the kinetics of β-catenin and Bcl-XL are initially consistent with a role in mediating survival. However, later in selection β-catenin may be more important in preventing cells that have been negatively signaled from maturing further, while Bcl-XL levels remain low, leading to their eventual death.eng
dc.format.extentv, 44 pageseng
dc.identifier.otherOlsonW-122011-T1319eng
dc.identifier.urihttp://hdl.handle.net/10355/14596eng
dc.publisherUniversity of Missouri--Columbiaeng
dc.relation.ispartof2011 Freely available theses (MU)eng
dc.relation.ispartofcommunityUniversity of Missouri-Columbia. Graduate School. Theses and Dissertations. Theses. 2011 Theseseng
dc.subjectthymic selectioneng
dc.subjectT-celleng
dc.subjectextra cellular regulated kinaseeng
dc.subjectcell deatheng
dc.titleThe roles of ERK pathway localization and the regulation of β-catenin/Bcl-XL kinetic in thymic selectioneng
dc.typeThesiseng
thesis.degree.disciplineMicrobiology (Medicine) (MU)eng
thesis.degree.grantorUniversity of Missouri--Columbiaeng
thesis.degree.levelMasterseng
thesis.degree.nameM.S.eng


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