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)
Type
Research Project (R01)
Project #
2R01EY015130-10
Application #
8751511
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Shen, Grace L
Project Start
Project End
Budget Start
Budget End
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
Wang, Haibo; Yang, Zhihong; Jiang, Yanchao et al. (2014) Quantitative analyses of retinal vascular area and density after different methods to reduce VEGF in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 55:737-44
Hartnett, M Elizabeth (2014) Vascular endothelial growth factor antagonist therapy for retinopathy of prematurity. Clin Perinatol 41:925-43
Hartnett, M Elizabeth; Morrison, Margaux A; Smith, Silvia et al. (2014) Genetic variants associated with severe retinopathy of prematurity in extremely low birth weight infants. Invest Ophthalmol Vis Sci 55:6194-203
Wang, Haibo; Jiang, Yanchao; Shi, Dallas et al. (2014) Activation of Rap1 inhibits NADPH oxidase-dependent ROS generation in retinal pigment epithelium and reduces choroidal neovascularization. FASEB J 28:265-74
Wang, Haibo; Yang, Zhihong; Jiang, Yanchao et al. (2014) Endothelial NADPH oxidase 4 mediates vascular endothelial growth factor receptor 2-induced intravitreal neovascularization in a rat model of retinopathy of prematurity. Mol Vis 20:231-41
Jiang, Yanchao; Wang, Haibo; Culp, David et al. (2014) Targeting Müller cell-derived VEGF164 to reduce intravitreal neovascularization in the rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 55:824-31
Young, Marielle P; Sawyer, Briana L; Hartnett, M Elizabeth (2014) Ophthalmologic findings in an 18-month-old boy with focal dermal hypoplasia. J AAPOS 18:205-7
Yang, Zhihong; Wang, Haibo; Jiang, Yanchao et al. (2014) VEGFA activates erythropoietin receptor and enhances VEGFR2-mediated pathological angiogenesis. Am J Pathol 184:1230-9
Wang, Haibo; Smith, George W; Yang, Zhihong et al. (2013) Short hairpin RNA-mediated knockdown of VEGFA in Muller cells reduces intravitreal neovascularization in a rat model of retinopathy of prematurity. Am J Pathol 183:964-74
Wang, Haibo; Zhang, Sarah X; Hartnett, Mary Elizabeth (2013) Signaling pathways triggered by oxidative stress that mediate features of severe retinopathy of prematurity. JAMA Ophthalmol 131:80-5

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