The IL-6 Induced Retinal Iron Sequestration Response

项目摘要 铁在健康和患病的视网膜中都起着关键作用。的长期目标 拟议的研究是为了了解炎症如何与视网膜疾病相关 促进铁失调，并发现如何防止视网膜铁毒性。铁是 视网膜中线粒体能量产生、膜合成和细胞增殖所必需的蛋白质。 视觉周期，但成为一个中央生产商的氧化应激时，调节不当。 铁毒性在视网膜疾病中是明显的，如下：1）铁引起快速视网膜变性 眼内异物进入眼内。2)人类AMD视网膜具有 铁含量高于年龄匹配的对照组，表明铁超载可能在AMD中发挥作用 发病机制3)与这一假设相一致，在遗传性疾病aceroplasminemia中， 铁氧化酶铜蓝蛋白（Cp）的缺失导致视网膜铁蓄积和早发性 黄斑变性4)敲除Cp及其同源物Hephaestin（Heph）的小鼠 年龄依赖性视网膜铁过载和退行性变，具有AMD的特征，包括 补体激活和视网膜下新生血管形成（导致湿性AMD）。最近 来自非眼细胞的证据表明，白细胞介素6（IL-6）可以触发“细胞铁 螯合反应”，以防止微生物获得他们需要的铁生长， 复制的这一点，结合眼内和血清IL-6水平升高的发现， 提示IL-6可能促进AMD患者视网膜铁超载。拟议的实验 本文将利用人iPSC-RPE细胞培养物、小鼠模型和死后人组织 以确定IL-6视网膜铁螯合反应。IL-6反式信号传导抑制剂 路将被测试。在激活或抑制IL-6通路后， 铁和它的运输商将进行评估。这些变化将与 AMD与正常死后视网膜。预计这些研究将导致 开发新的抗AMD方法，减少炎症诱导的铁 积累

PROJECT SUMMARY Iron plays a critical role in both the healthy and diseased retina. The long term goals of the proposed studies are to understand how inflammation associated with retinal disease promotes iron dysregulation, and discover how to protect against retinal iron toxicity. Iron is necessary in the retina for mitochondrial energy production, membrane synthesis and the visual cycle, but becomes a central producer of oxidative stress when improperly regulated. Iron toxicity is evident in retinal disease as follows: 1) Iron causes rapid retinal degeneration following entry into the eye carried by an intraocular foreign body. 2) Human AMD retinas have more iron than age-matched controls, suggesting that iron overload may play a role in AMD pathogenesis. 3) Consistent with this hypothesis, in the inherited disease aceruloplasminemia, loss of the ferroxidase ceruloplasmin (Cp) results in retinal iron accumulation and early onset macular degeneration. 4) Mice with knockout for Cp and its homolog hephaestin (Heph) have an age-dependent retinal iron overload and degeneration sharing features of AMD, including complement activation and subretinal neovascularization (which causes wet AMD). Recent evidence from non-ocular cells indicates that interleukin 6 (IL-6) can trigger a “cellular iron sequestration response” to prevent microbes from accessing the iron they need for growth and replication. This, combined with the finding of elevated intraocular and serum IL-6 levels in AMD, suggest that IL-6 may promote retinal iron overload in AMD. Experiments proposed herein will utilize human iPSC-RPE cell culture, mouse models, and post mortem human tissue to define the IL-6 retinal iron sequestration response. An inhibitor of the IL-6 trans-signaling pathway will be tested. Following activation or inhibition of IL-6 pathways, changes in the levels of iron and its transporters will be assessed. These changes will be correlated with those in AMD versus normal post mortem retinas. It is expected that these studies will lead to development of novel anti-AMD approaches that diminish inflammation-induced iron accumulation.