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沉重的经济负担。脂质失调和改变的巨噬细胞功能/炎症都与NV相关。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起重要作用。为了开发新的预防性治疗，而不是解决如何孤立地操纵每个相关的脂质或炎症途径，关键是定义全局影响脂质失调，改变巨噬细胞功能/极化和炎症的关键调节因子，以控制NV。我们和其他人鉴定了与脂质敏感核受体RORa相关的新生血管性AMD的遗传易感性，RORa可作为连接脂质代谢和巨噬细胞活化/炎症的全局调节剂。RORa作为转录因子，控制脂质代谢中许多基因的表达以及炎症细胞因子。我们的初步结果显示，RORa缺乏显著抑制氧诱导的增殖性视网膜病变（OIR）小鼠模型中的病理性视网膜NV，与促炎细胞因子的表达减少和抗炎细胞因子的表达增加相关。此外，我们发现RORa直接控制Socs 3（细胞因子信号转导抑制因子3）的转录，Socs 3是巨噬细胞极化和组织炎症的关键调节因子。我们假设RORa是一种新型的脂质敏感免疫调节剂，通过调节巨噬细胞极化以及促炎和抗炎细胞因子的分泌来控制视网膜和脉络膜NV的发展;靶向RORa可以全面治疗或预防NV。我们将以三个目标来检验这一假设。目标1：为了确定RORa是否控制病理性视网膜和脉络膜NV的发展，我们将在RORa缺陷小鼠中进一步表征具有OIR模型的病理性视网膜NV和具有激光诱导的新生血管性AMD CNV模型的脉络膜NV（CNV）。目标二：为了从机制上确定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，我们将评估具有OIR和CNV的全身性和巨噬细胞特异性RORa缺陷眼中的炎症特征和巨噬细胞极化，并在原代和分化的巨噬细胞培养物中通过RORa直接转录控制炎症因子和产生的巨噬细胞极化。目标3：为了鉴定抑制病理性视网膜和脉络膜NV的RORa药理学抑制剂，我们将评估新型合成的反向激动剂和RORa激动剂在OIR和激光诱导的CNV模型中的作用。这项工作将确定一种新的转录控制机制，它与改变炎症反应的脂质稳态失调，是否是重要的新生血管性眼病。如果成功，可以开发针对RORa的新治疗方法，以防止儿童和成人的NV致盲和视力丧失。

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.