The pathogenesis of retinal neovascularization in ROP is incompletely understood, although hypoxia is thought to be critical for its development. The long-term objective of this research is to understand better the role of hypoxia in retinal neovascularization so that more effective preventative, diagnostic and therapeutic strategies may be developed. During the previous funding period a novel MRI method was developed to non-invasively map the oxygenation rate along the two-dimensional extent of the retina. This method showed that an unusually slow retinal oxygenation rate was present in retinas before the development of ROP. This slow oxygenation rate is consistent with hypoxia, but it cannot yet be interpreted unambiguously as a measure of hypoxia. The present proposal seeks to confirm two hypotheses: (1) that abnormally slow oxygenation provides an indirect, yet specific measure of hypoxia and (2) that this MRI method has potential clinical utility for directing supplemental oxygen therapy.
Three specific aims will be addressed using this MRI method and a newborn rat model of ROP: (1) to determine the association between the preretinal vitreous retinal oxygen tension and oxygenation rate under normal and pathological conditions; (2) to determine if the change in retinal oxygenation that occurs during supplemental oxygen treatment is linear with supplemental dose and evolves during neovascularization; and (3) to determine the association between the retinal oxygenation rate measured before neovascularization and the level of supplemental oxygen needed to prevent vascular endothelial growth factor (VEGF) upregulation and neovascularization. The proposed studies will lay the groundwork for eventual clinical evaluation of similar MRI experiments in human ROP. This work may have broad impact beyond ROP since abnormal blood vessel growth is a common pathobiologic event for other blinding disorders, such as diabetic retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY010221-05
Application #
2701398
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1995-03-01
Project End
2002-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Wayne State University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Kern, T S; Tang, J; Berkowitz, B A (2010) Validation of structural and functional lesions of diabetic retinopathy in mice. Mol Vis 16:2121-31
Bissig, David; Berkowitz, Bruce A (2009) Manganese-enhanced MRI of layer-specific activity in the visual cortex from awake and free-moving rats. Neuroimage 44:627-35
Berkowitz, Bruce A; Gradianu, Marius; Bissig, David et al. (2009) Retinal ion regulation in a mouse model of diabetic retinopathy: natural history and the effect of Cu/Zn superoxide dismutase overexpression. Invest Ophthalmol Vis Sci 50:2351-8
Calkins, David J; Horner, Philip J; Roberts, Robin et al. (2008) Manganese-enhanced MRI of the DBA/2J mouse model of hereditary glaucoma. Invest Ophthalmol Vis Sci 49:5083-8
Berkowitz, Bruce A; Gradianu, Marius; Schafer, Stephen et al. (2008) Ionic dysregulatory phenotyping of pathologic retinal thinning with manganese-enhanced MRI. Invest Ophthalmol Vis Sci 49:3178-84
Berkowitz, Bruce A; Roberts, Robin; Stemmler, Ann et al. (2007) Impaired apparent ion demand in experimental diabetic retinopathy: correction by lipoic Acid. Invest Ophthalmol Vis Sci 48:4753-8
Luan, Hongmei; Leitges, Michael; Gupta, Rita R et al. (2004) Effect of PKCbeta on retinal oxygenation response in experimental diabetes. Invest Ophthalmol Vis Sci 45:937-42
Berkowitz, Bruce A; Roberts, Robin; Luan, Hongmei et al. (2004) Dynamic contrast-enhanced MRI measurements of passive permeability through blood retinal barrier in diabetic rats. Invest Ophthalmol Vis Sci 45:2391-8
Berkowitz, Bruce A; Luan, Hongmei; Gupta, Rita R et al. (2004) Regulation of the early subnormal retinal oxygenation response in experimental diabetes by inducible nitric oxide synthase. Diabetes 53:173-8
Berkowitz, Bruce A; Luan, Hongmei; Roberts, Robin L (2004) Effect of methylimidazole-induced hypothyroidism in a model of low retinal neovascular incidence. Invest Ophthalmol Vis Sci 45:919-21

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