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dc.contributor.authorPunareewattana, Korawuthen_US
dc.date.accessioned2014-03-14T20:10:19Z
dc.date.available2014-03-14T20:10:19Z
dc.date.issued2003-04-18en_US
dc.identifier.otheretd-04212003-173718en_US
dc.identifier.urihttp://hdl.handle.net/10919/27088
dc.description.abstractDiabetic embryopathy is a major complication of pregnant women with type I diabetes. Immune defects in the pathogenesis of diabetic embryopathy have been suggested. We hypothesized that activated immune system can counteract diabetic effect and result in prevention of diabetic embryopathy. Diabetes was induced in pregnant ICR mice by streptozocin injection. Three different techniques of maternal immune stimulation, complete Freundâ s adjuvant (CFA), granulocyte-macrophage colony-stimulating factor (GM-CSF), or interferon-gamma (IFN-g), were used to stimulate the maternal immune system. Approximately 50% of fetuses from hyperglycemic (>27 mM/L) dams were malformed, with neural tube defects predominating. Maternal immune stimulation during the time of normoglycemia, i.e. prior to onset of hyperglycemia, was necessary for reducing teratogenic effects associated with hyperglycemia. The immune-stimulated diabetic mice then produced significantly lower numbers of malformed fetuses: CFA 20.9%, GM-CSF 23.3%, IFN-g 13.9%. A gene microarray was then used to examine a selected panel of placental and splenic genes. We hypothesized that a shared profile of placental or splenic gene expression changes may correlate to the reduced birth defect outcome induced by the different immune stimulation procedures. Diabetes did not cause significant changes in placenta or spleen gene expression profile. In placenta, CFA and GM-CSF changed placental gene expression relative to control or diabetes, but differentially affected such genes relative to each other; further, IFN-g did not affect gene expression relative to control or diabetes. Thus no common pattern of improved placental cytokine, cell-cycle, apoptotic, transcription factor, or other gene expression was identified in the immune-stimulated mice. In spleen, all 3 immune activators produced a common altered gene expression profile. The overall gene expression profile after all immune stimulation procedures suggested increased splenocyte activity and cytokine production. The cytokine GM-CSF, in particular, was up-regulated in splenic leukocytes. This cytokine has previously been associated with reduced cleft palate in urethane-exposed mice after immune stimulation, and with reduced limb malformations in cyclophosphamide-treated mice after intra-uterine administration. In contrast, the TGF-beta3 gene was down-regulated in immune-stimulated diabetic mice. This gene was up-regulated in urethane-exposed mice, an effect that may be associated with reduced cleft palate. Thus unlike urethane, TGF-beta3 gene expression did not show a relationship with reduced diabetes-induced birth defects. Taken together, these data prove our hypotheses and suggest that mechanistically diverse forms of immune activation result in protection against diabetes-related teratogenesis, but only if given prior to onset of hyperglycemia. Such immune stimulation in mice may act through systemic immune organs, i.e. spleen, over-riding adverse effects of diabetes on development.en_US
dc.publisherVirginia Techen_US
dc.relation.haspartkpdissert.pdfen_US
dc.rightsI hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Virginia Tech or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.en_US
dc.subjectCFAen_US
dc.subjectGM-CSFen_US
dc.subjectTeratogenesisen_US
dc.subjectBirth defectsen_US
dc.subjectIFN-gammaen_US
dc.subjectImmune stimulationen_US
dc.subjectDiabetic embryopathyen_US
dc.subjectDiabetesen_US
dc.titleImmunoteratological Studies of Diabetic Embryopathy Using Gene Expression Analysisen_US
dc.typeDissertationen_US
dc.contributor.departmentVeterinary Medical Sciencesen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
dc.contributor.committeechairHolladay, Steven D.en_US
dc.contributor.committeememberRutherford, Charles L.en_US
dc.contributor.committeememberRobertson, John L.en_US
dc.contributor.committeememberEhrich, Marion F.en_US
dc.contributor.committeememberAhmed, S. Ansaren_US
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-04212003-173718/en_US
dc.date.sdate2003-04-21en_US
dc.date.rdate2004-04-23
dc.date.adate2003-04-23en_US


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