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Allosteric modulation of VLA-4 with the atypical antipsychotic thioridazine

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Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/17459

Allosteric modulation of VLA-4 with the atypical antipsychotic thioridazine

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Title: Allosteric modulation of VLA-4 with the atypical antipsychotic thioridazine
Author: Williams, Bart
Advisor(s): Sklar, Larry
Committee Member(s): Wharton, Walker
Chigaev, Alexandre
Department: University of New Mexico. Biomedical Sciences Graduate Program
Subject(s): integrin
stem cell
vla-4
phenothiazine
LC Subject(s): Thioridazine.
Integrins--Inhibitors.
Allosteric regulation.
Degree Level: Masters
Abstract: A recent primary drug screen by the University of New Mexico Center for Molecular Discovery uncovered a novel group of allosteric-modulators of VLA-4 integrins known as phenothiazines. Phenothiazine family compounds were initially discovered as organic dyes in the 1800's, the most well-known of which is methylene blue. Relatively soon thereafter phenothiazines were found to be useful clinically, a trend that has continued in the century since peaking as antipsychotics in the 1950's. Today, phenothiazines are still being pursued clinically as seen in a number of recent patents for phenothiazine use in autoimmune disorders. This study sought to further characterize the newly discovered relationship between phenothiazines and VLA-4 integrin in a stepwise progression from in vitro experiments to an in vivo animal model. Here, it is shown that the phenothiazine compound thioridazine causes broad inhibition of adhesion related activity including: the rapid interruption of VLA-4 bound uorescent molecules, the disaggregation of VLA-4 and VCAM-1 attached cells, rapid reduction in intracellular calcium signaling, and loss of cellular motility to G i chemokines. Furthermore, it is shown that thioridazine treatment can cause a 3-fold increase in mobilization of murine hematopoietic stem and progenitor cells. Combined, these data answer forty year old questions about the nature of phenothiazine treatment, provide insight in to the mechanism of action and provide evidence for the potential of VLA-4 allosteric modulators in vivo.
Graduation Date: December 2011
URI: http://hdl.handle.net/1928/17459

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