The IL-6 Induced Retinal Iron Sequestration Response

IL-6 诱导的视网膜铁螯合反应

基本信息

批准号：
10636913
负责人：
JOSHUA L DUNAIEF
金额：
$ 40.12万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10636913
关键词：
Aceruloplasminemia Adaptive Immune System Affect Age Age related macular degeneration Aqueous Humor Astrocytes Atrophic Autopsy Binding Bruch&apos s basal membrane structure Cell Culture Techniques Cell Surface Receptors Cell surface Cells Ceruloplasmin Choroid Chronic Complement Activation Complex Data Development Disease Down-Regulation Drusen Enzyme-Linked Immunosorbent Assay Eye Foreign Bodies Glaucoma Glial Fibrillary Acidic Protein Goals Growth Health Hereditary Disease Homeostasis Homologous Gene Host Defense Mechanism Human Hypertrophy IL-6 inhibitor IL6 gene IL6ST gene Inductively Coupled Plasma Mass Spectrometry Inflammation Inflammatory Injections Innate Immune System Interleukin 6 Receptor Interleukin-1 beta Interleukin-6 Iron Iron Overload Knock-out Knockout Mice Lead Link Lipids Macular degeneration Measures Mediating Messenger RNA Microbe Mitochondria Muller&apos s cell Mus Neural Retina Oxidative Stress Pathogenesis Pathway interactions Patients Phase I Clinical Trials Photoreceptors Play Production Proteins Regulation Retina Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Role SLC11A2 gene Serum Signal Pathway Signal Transduction Specificity Stains Structure TNF gene Testing Toxic effect Transgenic Mice Up-Regulation Vascular Endothelial Growth Factors Work age related cell type cytokine early onset experimental study extracellular human tissue induced pluripotent stem cell inhibitor intravenous injection intravitreal injection membrane synthesis metal transporting protein 1 mouse model neovascularization novel novel therapeutic intervention oxidative damage prevent receptor response visual cycle

项目摘要

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.

项目摘要铁在健康和解散的视网膜中都起着至关重要的作用。长期目标拟议的研究是了解与残留疾病有关的炎症如何促进铁失调，并发现如何防止残留铁毒性。铁是在视网膜中需要进行线粒体能量产生，膜合成和视觉周期，但是当不当调节时，会成为氧化应激的中心产生者。铁毒性是残留疾病中的证据：1）铁导致快速残留变性在进入眼内异物携带的眼睛之后。 2）人类AMD视网膜有铁比年龄匹配的控件多，这表明铁超负荷可能在AMD中起作用发病。 3）与这一假设一致，在遗传性疾病的抗衰素血症中铁氧化酶Ceruroplasmin（CP）的丧失导致残留的铁积累和早期发作黄斑变性。 4）CP及其同源性hephaestin（Heph）的小鼠有与年龄有关的视网膜铁超载和AMD的变性共享特征，包括补体激活和视网膜下新生血管形成（导致湿AMD）。最近的来自非眼细胞的证据表明白介素6（IL-6）可以触发“细胞铁隔离响应”，以防止微生物获得生长所需的铁和复制。这与发现眼内和血清IL-6水平升高相结合 AMD，建议IL-6可以促进AMD中的残留铁超载。提出了实验这里将利用人类IPSC-RPE细胞培养，小鼠模型和验尸后人体组织定义IL-6视网膜铁疗法。 IL-6反体信号的抑制剂路径将进行测试。激活或抑制IL-6途径后，水平的变化将评估铁及其转运蛋白的。这些更改将与其中的更改相关 AMD与正常的验尸视网膜。预计这些研究将导致开发新的抗AMD方法，减少了炎症引起的铁积累。