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.
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.
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