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作者 Graham, W. Vallen
書名 Molecular mechanisms of epithelial MLCK isoform regulation: Characterization and pharmacological exploitation
國際標準書號 9781124048659
book jacket
說明 193 p
附註 Source: Dissertation Abstracts International, Volume: 71-07, Section: B, page: 4059
Adviser: Jerrold R. Turner
Thesis (Ph.D.)--The University of Chicago, 2010
The molecular events surrounding TNF-mediated tight junction regulation are the focus of this dissertation. Exposure of cultured epithelial monolayers to TNF in vitro can cause barrier loss. This tight junction regulation occurs within hours and is mediated by myosin light chain kinase (MLCK), which phosphorylates myosin II regulatory light chain (MLC). The mechanisms by which TNF activates MLCK may include initiation of an increase in intracellular Ca2+, but this has not been reported in intestinal epithelium. However, it is clear that TNF induces transcriptional activation of MLCK, both in human intestinal epithelial cell lines in vitro and in mouse enterocytes in vivo. Moreover, this process appears to be active in human inflammatory bowel disease patients in vivo, as intestinal epithelial MLCK expression and MLC phosphorylation are both increased in association with active disease. The data discussed here describe the molecular events in MLCK transcriptional activation and the novel observation that MLCK1 is trafficked to the perijunctional actomyosin ring in response to TNF signaling. Furthermore, I describe here, unique tools for studying MLCK1 trafficking and activity. Targeting MLCK1-specific trafficking with small molecule drugs reverses TNF-induced barrier dysfunction in vitro and in vivo. Therefore, not only are these drugs powerful tools in understanding molecular mechanisms that regulate MLCK1, but may also represent a therapeutic alternative to the current IBD treatment regimen of immune suppression
School code: 0330
Host Item Dissertation Abstracts International 71-07B
主題 Biology, General
Biology, Molecular
Biology, Cell
0306
0307
0379
Alt Author The University of Chicago. Pathology
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