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dc.contributor.authorGu, Xiaolin
dc.date.accessioned2015-03-03T03:55:22Z
dc.date.available2015-03-03T03:55:22Z
dc.date.issued2001-11en
dc.identifier.urihttp://hdl.handle.net/10675.2/345984
dc.description.abstractThe overall goal of this study was to explore the possible molecular mediators of vaso-obliteration in retinopathy o f prematurity. Vaso-obliteration is the early hyperoxiainduced pathology. It leads to the later relative hypoxia in the retina tissue, because the insufficient blood supply cannot meet the increasing demands o f oxygen from the developing retina. Such retinal hypoxia then causes the blinding outcome through the formation o f neovessels and subsequent vitreous bleeding and fibrotic change in both retina and vitreous. Therefore, identification o f the possible mediators o f hyperoxiainduced vaso-obliteration will help us to understand more about the pathogenesis o f ROP and provide new and better strategies of treating and preventing this disease. Previous studies have shown that administration o f exogenous antioxidants can attenuate retinopathy in certain animal models and that hyperoxia is able to upregulate the expression and activity o f eNOS in vascular endothelial cells (Liao et al., 1995; North et al., 1996; Phelan and Faller, 1996). Hyperoxia also increases formation o f O2 ' which rapidly combines with NO to form the highly reactive oxidant ONOO*. Therefore, it is hypothesized that the NO and O2 'derived oxidant, ONOO', play an important role in the initial vascular injury leading to obliteration of the developing retinal capillaries in oxygen-induced retinopathy (OIR). It is further proposed that ONOO' causes vascular injury by modifying the critical intracellular signaling pathway that controls endothelial cell survival (Fig 5). This hypothesis has been tested by accomplishing the following specific aims: 1. Establish the OIR mouse model for ROP. Analyze NOS expression and assay the formation of NO and ONOO' in the vaso-obliteration phase o f OIR. 2. Determine whether deletion o f the eNOS or iNOS gene alters the vaso-obliteration phase o f OIR. If so, determine whether the gene deletion also reduces ONOO' formation in the vaso-obliteration phase o f OIR. 3. Test whether or not pharmacological inhibition o f NOS reduces vascular obliteration in wild-type mice with OIR. 4. Establish a tissue culture model for oxygen-induced endothelial cell injury. Determine the effect o f hyperoxia on endothelial cell survival and test whether the effects are mediated by NO, O2 ', and /or ONOO'. 5. Test whether ONOO' alters the signal transduction pathway for endothelial cell survival by altering the activity o f PI3K/AKT.
dc.relation.urlhttp://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/304734022?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.subjectretinopathy of prematurityen
dc.subjectRetinaen
dc.subjectNitric oxide synthase (NOS)en
dc.subjectapoptosisen
dc.subjectKinase Signaling Pathwayen
dc.titleMechanisms of Vessel Obliteration in Oxygen-Induced Retinopathyen
dc.typeDissertationen
dc.contributor.departmentVascular Biology Centeren
dc.description.advisorCaldwell, Ruth B.en
dc.description.degreeDoctor of Philosophy (Ph.D.)en
dc.description.committeeSmith, Sylvia B.; Atherton, Sally S.; Liou, Gregory I. H.; Calwell, Robert W.en
html.description.abstractThe overall goal of this study was to explore the possible molecular mediators of vaso-obliteration in retinopathy o f prematurity. Vaso-obliteration is the early hyperoxiainduced pathology. It leads to the later relative hypoxia in the retina tissue, because the insufficient blood supply cannot meet the increasing demands o f oxygen from the developing retina. Such retinal hypoxia then causes the blinding outcome through the formation o f neovessels and subsequent vitreous bleeding and fibrotic change in both retina and vitreous. Therefore, identification o f the possible mediators o f hyperoxiainduced vaso-obliteration will help us to understand more about the pathogenesis o f ROP and provide new and better strategies of treating and preventing this disease. Previous studies have shown that administration o f exogenous antioxidants can attenuate retinopathy in certain animal models and that hyperoxia is able to upregulate the expression and activity o f eNOS in vascular endothelial cells (Liao et al., 1995; North et al., 1996; Phelan and Faller, 1996). Hyperoxia also increases formation o f O2 ' which rapidly combines with NO to form the highly reactive oxidant ONOO*. Therefore, it is hypothesized that the NO and O2 'derived oxidant, ONOO', play an important role in the initial vascular injury leading to obliteration of the developing retinal capillaries in oxygen-induced retinopathy (OIR). It is further proposed that ONOO' causes vascular injury by modifying the critical intracellular signaling pathway that controls endothelial cell survival (Fig 5). This hypothesis has been tested by accomplishing the following specific aims: 1. Establish the OIR mouse model for ROP. Analyze NOS expression and assay the formation of NO and ONOO' in the vaso-obliteration phase o f OIR. 2. Determine whether deletion o f the eNOS or iNOS gene alters the vaso-obliteration phase o f OIR. If so, determine whether the gene deletion also reduces ONOO' formation in the vaso-obliteration phase o f OIR. 3. Test whether or not pharmacological inhibition o f NOS reduces vascular obliteration in wild-type mice with OIR. 4. Establish a tissue culture model for oxygen-induced endothelial cell injury. Determine the effect o f hyperoxia on endothelial cell survival and test whether the effects are mediated by NO, O2 ', and /or ONOO'. 5. Test whether ONOO' alters the signal transduction pathway for endothelial cell survival by altering the activity o f PI3K/AKT.


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