Pathologic retinal neovascularization (NV) causes profound visual loss in age-related macular degeneration (AMD), diabetic retinopathy and retinopathy of prematurity. Vision loss imposes high economic burdens on families and society. Both lipid dysregulation and altered macrophage function/inflammation are associated with NV. Phenotypically plastic macrophages play important roles in regulating ocular angiogenesis during development and in pathologies. In order to develop novel preventative treatment, rather than addressing how to manipulate each relevant lipid or inflammatory pathway in isolation, it is critical to define the key regulators that globally influence lipid dysregulation, altered macrophage function/polarization and inflammation in the eye to control NV. We and others identified a genetic predisposition to neovascular AMD with links to a lipid- sensing nuclear receptor RORa, which may act as a global regulator linking lipid metabolism and macrophage activation/inflammation. RORa, functioning as a transcription factor, controls expression of numerous genes in lipid metabolism, as well as inflammatory cytokines. Our preliminary results show that RORa deficiency significantly suppresses pathologic retinal NV in a mouse model of oxygen-induced proliferative retinopathy (OIR), associated with decreased expression of pro-inflammatory cytokines and increased anti-inflammatory cytokines. Moreover, we find RORa directly controls transcription of Socs3 (suppressor of cytokine signaling 3), a critical regulatorof macrophage polarization and tissue inflammation. We hypothesize that RORa, a novel lipid-sensing immuno-regulator, controls the development of retinal and choroidal NV, by modulating macrophage polarization and secretion of pro- and anti-inflammatory cytokines; targeting RORa may comprehensively treat or prevent NV. We will test this hypothesis with three aims.
Aim 1 : To determine if RORa controls the development of pathologic retinal and choroidal NV, we will further characterize in RORa deficient mice pathologic retinal NV with an OIR model and choroidal NV (CNV) with a laser-induced CNV model of neovascular AMD.
Aim 2 : To determine mechanistically if RORa controls ocular NV through modulation of macrophage polarization and retinal inflammation, we will evaluate inflammatory profile and macrophage polarization in systemic and macrophage specific RORa deficient eyes with OIR and CNV, and direct transcriptional control of inflammatory factors and resulting macrophage polarization by RORa in primary and differentiated macrophage culture.
Aim 3 : To identify pharmacologic suppressors of RORa that inhibit pathologic retinal and choroidal NV, we will assess the effects of novel synthetic inverse agonists and an agonist of RORa in OIR and laser-induced CNV models. This work will determine whether a novel transcriptional control mechanism, which links dysregulation of lipid homeostasis with altered inflammatory responses, is important for neovascular eye diseases. If successful, new treatments targeting RORa may be developed to prevent blinding NV and vision loss in children and adults.

Public Health Relevance

The broad goal of this study is to investigate the role of nuclear receptor in mediating pathologic ocular neovascularization, a major cause of blindness in children and adults. The proposed project specifically aims to investigate the effect of a lipid sensing nuclear receptor RORa in modulating macrophage polarization and inflammation to control pathologic neovascularization. Targeting this novel nuclear receptor may lead to design of new therapeutic approaches for treating vascular eye diseases such as age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity. The relevance to public health would be to use the results from this study and develop new therapies that will effectively prevent or treat blinding pathologic neovascularization, a leading cause of vision loss.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY024963-03
Application #
9189618
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2014-12-02
Project End
2019-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Joyal, Jean-Sébastien; Sun, Ye; Gantner, Marin L et al. (2016) Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1. Nat Med 22:439-45
Liu, Chi-Hsiu; Wang, Zhongxiao; Sun, Ye et al. (2016) Retinal expression of small non-coding RNAs in a murine model of proliferative retinopathy. Sci Rep 6:33947
Wang, Zhongxiao; Liu, Chi-Hsiu; Sun, Ye et al. (2016) Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy. Am J Pathol 186:2588-600
Sun, Ye; Liu, Chi-Hsiu; SanGiovanni, John Paul et al. (2015) Nuclear receptor RORα regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation. Proc Natl Acad Sci U S A 112:10401-6
Gong, Yan; Li, Jie; Sun, Ye et al. (2015) Optimization of an Image-Guided Laser-Induced Choroidal Neovascularization Model in Mice. PLoS One 10:e0132643
Liu, Chi-Hsiu; Sun, Ye; Li, Jie et al. (2015) Endothelial microRNA-150 is an intrinsic suppressor of pathologic ocular neovascularization. Proc Natl Acad Sci U S A 112:12163-8
Wang, Zhongxiao; Cheng, Rui; Lee, Kyungwon et al. (2015) Nanoparticle-mediated expression of a Wnt pathway inhibitor ameliorates ocular neovascularization. Arterioscler Thromb Vasc Biol 35:855-64
SanGiovanni, John Paul; Chen, Jing; Gupta, Ankur S et al. (2015) Netrin-1 - DCC Signaling Systems and Age-Related Macular Degeneration. PLoS One 10:e0125548
Sun, Ye; Ju, Meihua; Lin, Zhiqiang et al. (2015) SOCS3 in retinal neurons and glial cells suppresses VEGF signaling to prevent pathological neovascular growth. Sci Signal 8:ra94
Fu, Zhongjie; Lofqvist, Chatarina A; Shao, Zhuo et al. (2015) Dietary ω-3 polyunsaturated fatty acids decrease retinal neovascularization by adipose-endoplasmic reticulum stress reduction to increase adiponectin. Am J Clin Nutr 101:879-88

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