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dc.contributor.authorBehl, Yugalen_US
dc.date.accessioned2019-12-16T15:40:42Z
dc.date.available2019-12-16T15:40:42Z
dc.date.issued2007
dc.date.submitted2007
dc.identifier.other(OCoLC)234379895
dc.identifier.other(OCoLC)234379895
dc.identifier.otherb27874850
dc.identifier.urihttps://hdl.handle.net/2144/38829
dc.descriptionPLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact open-help@bu.edu.en_US
dc.descriptionThesis (D.Sc.)--Henry M. Goldman School of Dental Medicine, 2007 (Periodontology and Oral Biology).en_US
dc.descriptionIncludes bibliography: leaves 141-158.en_US
dc.description.abstractMicrovascular cell loss plays a critical role in the pathogenesis of diabetic retinopathy, an important cause of blindness. To investigate molecular mechanisms responsible for diabetes-increased microvascular cell death animal models of both type 1 and type 2 diabetes were used to investigate the role of elevated TNF-[alpha] and FOXO1 activity in the retinas of diabetic rats. Inhibition of TNF by pegsunercept in vivo significantly reduced diabetes-enhanced FOXO1 activation and microvascular cell apoptosis in both type 1 and type 2 diabetes. Pegsunercept also reduced the formation of pericyte ghosts and acellular capillaries; characteristic lesions of early diabetic retinopathy in both type l and type 2 diabetes. The relationship between high glucose, TNF-[alpha] and FOXO1 in retinal microvascular endothelial cells was further investigated in vitro. High glucose induced apoptosis that was TNF dependent through a mechanism that invoIved activation of FOXO1. By siRNA and focused microarrays several classes of genes that regulate endothelial cells were induced by TNF-[alpha] and high glucose in vitro and many of the genes induced by high glucose were FOXO1 dependent. Intravitreal injection of FOXO1 siRNA in vivo significantly reduced diabetes enhanced apoptosis of retinal microvascular cells and subsequent pericyte ghost formation and acellular capillary formation in type 1 model of diabetes. FOXO1 silencing in vivo reduced retinal microvascular cell apoptosis in type 2 model also. These results demonstrate a previously unrecognized role for FOXO1 and TNF-α in promoting the early pathogenesis of diabetic retinopathy and demonstrate the potential therapeutic benefit of modulating their activity.en_US
dc.language.isoen_US
dc.publisherBoston Universityen_US
dc.rightsThis work is protected by copyright. Downloading is restricted to the BU community. If you are the author of this work and would like to make it publicly available, please contact open-help@bu.edu.en_US
dc.subjectDiabetic retinopathyen_US
dc.subjectForkhead transcription factorsen_US
dc.subjectTumor necrosis factors--alpha.en_US
dc.titleDiabetes-enhanced fox 01 activation induces retinal microvascular cell loss and is mediated by TNF-[alpha] in experimental diabetic retinopathyen_US
dc.typeThesis/Dissertationen_US
etd.degree.nameDoctor of Science in Oral Biologyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplinePeriodontology and Oral Biologyen_US
etd.degree.grantorBoston Universityen_US
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