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
Simmons, Aaron B; Bretz, Colin A; Wang, Haibo et al. (2018) Gene therapy knockdown of VEGFR2 in retinal endothelial cells to treat retinopathy. Angiogenesis 21:751-764
Bretz, Colin A; Divoky, Vladimir; Prchal, Josef et al. (2018) Erythropoietin Signaling Increases Choroidal Macrophages and Cytokine Expression, and Exacerbates Choroidal Neovascularization. Sci Rep 8:2161
Becker, Silke; Wang, Haibo; Simmons, Aaron B et al. (2018) Targeted Knockdown of Overexpressed VEGFA or VEGF164 in M√ľller cells maintains retinal function by triggering different signaling mechanisms. Sci Rep 8:2003
Wang, Haibo; Hartnett, M Elizabeth (2017) Roles of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase in Angiogenesis: Isoform-Specific Effects. Antioxidants (Basel) 6:
Becker, Silke; Wang, Haibo; Yu, Baifeng et al. (2017) Protective effect of maternal uteroplacental insufficiency on oxygen-induced retinopathy in offspring: removing bias of premature birth. Sci Rep 7:42301
Zhu, Weiquan; Shi, Dallas S; Winter, Jacob M et al. (2017) Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy. J Clin Invest 127:4569-4582
Todorich, Bozho; Thanos, Aristomenis; Yonekawa, Yoshihiro et al. (2017) Correspondence. Retina 37:e52-e54
Hartnett, Mary Elizabeth (2017) Advances in understanding and management of retinopathy of prematurity. Surv Ophthalmol 62:257-276
Shulman, Julia P; Weng, Cindy; Wilkes, Jacob et al. (2017) Association of Maternal Preeclampsia With Infant Risk of Premature Birth and Retinopathy of Prematurity. JAMA Ophthalmol 135:947-953
Becker, Silke; Wang, Haibo; Stoddard, Gregory J et al. (2017) Effect of subretinal injection on retinal structure and function in a rat oxygen-induced retinopathy model. Mol Vis 23:832-843

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