Retinopathy of prematurity (ROP) is a leading cause of childhood blindness world-wide. Our lab studies two important sequential phases of ROP: Phase I, in which physiologic retinal vascular development (PRVD) is delayed;followed by Phase II, in which vaso-proliferative intra-vitreal neovascularization (IVNV) increases risk of blindness. Standard-of-care laser treatment and anti-angiogenic strategies intended to treat Phase II, such as inhibitors of vascular endothelial growth factor (VEGF), are destructive of developing retinal tissue or delay PRVD, thereby prolonging Phase I;treatments intended to reduce the delay period of Phase I and to advance PRVD, can worsen IVNV in Phase II. Clinically, one wishes to inhibit IVNV but not interfere with PRVD in developing preterm infants. Work in the previous grant period identified targets to inhibit IVNV safely using a rat model of ROP and led to the following mechanistic hypotheses: VEGF produced by Muller cells (MCs) promotes survival in photoreceptors, retinal neurons, and MCs, but also binds VEGF receptor 2 in endothelial cells (ECs) to activate the erythropoietin receptor (EPOR) and/or NOX4/NADPH oxidase. Interactions between VEGFR2 and EPOR or NOX4 exacerbate EC-STAT3, which causes phase II IVNV. We also developed a method to study molecular mechanisms in the rat model of ROP using lentiviral gene therapy and polymerase II promoters targeting specifically MCs or ECs, which drive shRNAs efficiently when embedded in microRNA30 (miR30).
Specific Aim 1 is to test if knockdown of VEGF164 in MCs to retinal VEGF levels that inhibit IVNV and not delay PRVD will allow retinal neuronal survival and function.
Specific Aim 2 is to test if knockdown of EPOR in ECs will reduce IVNV in phase II ROP and not delay PRVD in phase I.
Specific Aim 3 is to test if STAT3 knockdown in ECs will inhibit IVNV and not delay PRVD. We will also test whether a drug treatment to regulate NOX4/VEGFR2-mediated STAT3 activation can inhibit phase II IVNV. Methods include: lentiviral gene therapy techniques;oxygen-induced retinopathy models in rat (50/10 """"""""ROP"""""""") and in transgenic mice;Micron III imaging;sub retinal injections;optical coherence tomography;electroretinography;immunohistochemistry of flat mounts and sections;western blot, real-time PCR.

Public Health Relevance

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide. One factor that causes severe ROP is vascular endothelial growth factor (VEGF), but VEGF is also important for normal development of the preterm infant eye. Methods to inhibit VEGF may pose safety concerns to the preterm infant. Our lab studies methods to regulate VEGF signaling to prevent severe ROP without adversely affecting development.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY015130-10
Application #
8751511
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Shen, Grace L
Project Start
2003-12-01
Project End
2019-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Utah
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Hartnett, M Elizabeth; Capone Jr, Antonio (2016) Advances in diagnosis, clinical care, research, and treatment in retinopathy of prematurity. Eye Brain 8:27-29
Wang, Haibo; Han, Xiaokun; Bretz, Colin A et al. (2016) Retinal pigment epithelial cell expression of active Rap 1a by scAAV2 inhibits choroidal neovascularization. Mol Ther Methods Clin Dev 3:16056
Wang, Haibo; Han, Xiaokun; Wittchen, Erika S et al. (2016) TNF-α mediates choroidal neovascularization by upregulating VEGF expression in RPE through ROS-dependent β-catenin activation. Mol Vis 22:116-28
Hartnett, Mary Elizabeth (2016) ADVANCES IN UNDERSTANDING AND MANAGEMENT OF RETINOPATHY OF PREMATURITY. Surv Ophthalmol :
Wang, Haibo; Han, Xiaokun; Kunz, Eric et al. (2016) Thy-1 Regulates VEGF-Mediated Choroidal Endothelial Cell Activation and Migration: Implications in Neovascular Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 57:5525-5534
Wang, Haibo; Hartnett, M Elizabeth (2016) Regulation of signaling events involved in the pathophysiology of neovascular AMD. Mol Vis 22:189-202
Carpenter, Delesha M; Tudor, Gail E; Sayner, Robyn et al. (2015) Exploring the influence of patient-provider communication on intraocular pressure in glaucoma patients. Patient Educ Couns :
Sayner, Robyn; Carpenter, Delesha M; Blalock, Susan J et al. (2015) Accuracy of Patient-reported Adherence to Glaucoma Medications on a Visual Analog Scale Compared With Electronic Monitors. Clin Ther 37:1975-85
Hartnett, M Elizabeth (2015) Pathophysiology and mechanisms of severe retinopathy of prematurity. Ophthalmology 122:200-10
Basilius, Jacob; Young, Marielle P; Michaelis, Timothy C et al. (2015) Structural Abnormalities of the Inner Macula in Incontinentia Pigmenti. JAMA Ophthalmol 133:1067-72

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