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Cover for THE CX3CR1+ LAMINA PROPRIA DENDRITIC CELL: MASTER SENTINEL OF THE TERMINAL ILEUM
dc.contributor.advisorGallicano, Ianen
dc.contributor.advisorCrooke, Elliotten
dc.creatoren
dc.date.accessioned2013-05-02T14:35:08Zen
dc.date.available2013-05-02T14:35:08Zen
dc.date.created2012en
dc.date.issueden
dc.date.submitted01/01/2011en
dc.identifier.otherAPT-BAG: georgetown.edu.10822_557511.tar;APT-ETAG: fd3dfcf9a23f26b81c446d3e975b79f1; APT-DATE: 2017-01-30_16:14:24en
dc.identifier.urien
dc.descriptionPh.D.en
dc.description.abstractThe CX3CR1+ lamina propria dendritic cell (LPDC) of the terminal ileum provides a unique sentinel role, critical for intestinal health. Here, we demonstrate that three Crohn's disease associated single nucleotide polymorphisms within the muramyl dipeptide receptor (MDP), NOD2, appear to alter the physical phenotype and transcriptome of the LPDC within the small intestine. Among the alterations described here, is a LPDC that is unable to extend its defining trans-epithelial dendrites (TEDs) into the lumen of the bowel despite (1) increased expression of the CX3CR1 receptor, (2) the presence of increased bacteria adherent to the mucosal wall and (3) the increased expression of the stress fractalkine, CX3CL1, all of which are directly associated with TED extension. In addition, the mRNA and protein expression profiles of the LPDC are also significantly distorted, including under-expression of genes within the TLR, ICAM and MIF families. There is also over expression of some inflammatory cytokines, such as IFN-ã and TNF-á, when comparing NOD2 mutants to wild types. Finally, the NOD2 mutation within the CX3CR1+ LPDC appears to depress Wnt5a expression both in vivo and in response to ex vivo MDP stimulation. In vivo observation of the Wnt5a/disheveled-2 axis showed reduced activation within the epithelium when in communication with the NOD2 mutant LPDC. However, once removed from the lamina propria compartment, the epithelium responded to Wnt5a stimulation by augmenting the transcription of Tcf4, a Paneth cell dependent transcription factor involved directly in the expression of human alpha defensin 5. We propose that Wnt5a participates in a novel homeostatic circuit involving the LPDC, epithelium, and Paneth cell and that a mutation in the NOD2 receptor within this LPDC alters its ability to communicate with its immunologic epithelial counterparts allowing for bacterial infiltration of the mucosal niche.en
dc.formatPDFen
dc.format.extent148 leavesen
dc.languageenen
dc.publisherGeorgetown Universityen
dc.sourceGeorgetown University-Graduate School of Arts & Sciencesen
dc.sourceBiochemistry & Molecularen
dc.subjectBacteriaen
dc.subjectCX3CR1en
dc.subjectDendritic Cellen
dc.subjectIntestinal Transplanten
dc.subjectNOD2en
dc.subjectTransepithelial Dendriteen
dc.subject.lcshMedicineen
dc.subject.lcshCytologyen
dc.subject.lcshMolecular biologyen
dc.subject.otherMedicineen
dc.subject.otherCellular biologyen
dc.subject.otherMolecular biologyen
dc.titleTHE CX3CR1+ LAMINA PROPRIA DENDRITIC CELL: MASTER SENTINEL OF THE TERMINAL ILEUMen
dc.typethesisen


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