Nuclear receptor mediated ocular neovascularization

描述（由申请人提供）：病理性视网膜新生血管（NV）导致年龄相关性黄斑变性（AMD）、糖尿病性视网膜病变和早产儿视网膜病变的严重视力丧失。视力丧失给家庭和社会带来了沉重的经济负担。脂质失调和巨噬细胞功能改变/炎症都与NV有关。表型可塑性巨噬细胞在发育和病理过程中调节眼部血管生成中发挥重要作用。为了开发新的预防性治疗方法，而不是解决如何单独操纵每个相关的脂质或炎症途径，关键是要确定影响脂质失调、巨噬细胞功能/极化改变和眼睛炎症的关键调节因子，以控制NV。我们和其他人发现了与脂质敏感核受体RORa相关的新血管性AMD的遗传易感性。它可能是连接脂质代谢和巨噬细胞激活/炎症的全局调节剂。RORa作为一种转录因子，控制着脂质代谢和炎症细胞因子中许多基因的表达。我们的初步结果表明，在氧诱导的增殖性视网膜病变（OIR）小鼠模型中，RORa缺乏显著抑制病理性视网膜NV，与促炎细胞因子表达减少和抗炎细胞因子表达增加有关。此外，我们发现RORa直接控制Socs3（细胞因子信号传导抑制因子3）的转录，Socs3是巨噬细胞极化和组织炎症的关键调节因子。我们假设RORa是一种新型的脂敏感免疫调节剂，通过调节巨噬细胞极化和促炎性和抗炎性细胞因子的分泌来控制视网膜和脉络膜NV的发展；针对RORa可以全面治疗或预防NV。我们将从三个方面验证这一假设。目的1：为了确定RORa是否控制病理性视网膜和脉络膜NV的发展，我们将用OIR模型进一步表征RORa缺陷小鼠的病理性视网膜NV，并用激光诱导的新生血管性AMD CNV模型进一步表征脉络膜NV （CNV）。目的2：为了确定RORa是否通过调节巨噬细胞极化和视网膜炎症来控制眼部NV的机制，我们将评估系统性和巨噬细胞特异性RORa缺陷眼的炎症特征和巨噬细胞极化，以及在原代和分化巨噬细胞培养中，RORa直接转录控制炎症因子和由此产生的巨噬细胞极化。目的3：为了确定抑制病理性视网膜和脉络膜NV的RORa药物抑制剂，我们将评估新型合成逆激动剂和RORa激动剂在OIR和激光诱导CNV模型中的作用。这项工作将确定一种新的转录控制机制，它将脂质稳态失调与炎症反应改变联系起来，对新生血管性眼病是否重要。如果成功，针对RORa的新治疗方法可能会被开发出来，以防止儿童和成人的致盲性NV和视力丧失。

DESCRIPTION (provided by applicant): 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.