Oxidative stress and innate immunity impair the visual cycle

氧化应激和先天免疫会损害视觉周期

• 批准号: 10117256
• 负责人: James T Handa
• 金额: $ 53.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117256
• 关键词: 11 cis Retinal; Acute; Address; Affect; Age related macular degeneration; Antioxidants; Area; Binding; Blindness; CD46 Antigen; Cells; Chronic; Complement; Complement Activation; Data; Disease; Elderly; Epitopes; Functional disorder; Gene Expression; Genes; Genetic; Impairment; Inflammation; Inflammatory; Injections; Injury; Ligands; Link; Literature; Malondialdehyde; Mediating; Micronutrients; Mus; Mutation; Natural Immunity; Oxidative Stress; Pathway interactions; Recycling; Research; Retina; Risk; Rodent; Role; Signal Transduction; Structure of retinal pigment epithelium; System; Testing; Vision; Visual; Visual Pathways; Visual impairment; Work; aging population; bevacizumab; cytokine; design; effective therapy; gene function; induced pluripotent stem cell; innovation; neovascular; notch protein; novel; prevent; retinal damage; sight restoration; targeted treatment; transcription factor; visual control; visual cycle

Project Summary Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. At present, no therapy will restore vision with any form of AMD. To address this shortcoming, this proposal will focus on mechanisms that could restore vision. The recycling of 11-cis-retinal (11-cRAL) by the visual cycle is an RPE function that is essential for vision. While oxidative stress and complement are integral factors in AMD pathophysiology, their impact on the visual cycle is undefined. The objective of this proposal is to define how oxidative stress and innate immunity impair the visual cycle to decrease vision in AMD. The hypothesis to be tested is that oxidative stress and impaired complement regulators Cfh and CD46 decrease the visual cycle network. The proposed specific aims are: 1. Determine the extent that oxidative stress i) impairs Cfh to induce inflammation which decreases visual cycle gene expression, and ii) induces Ptx3, and by regulating Cfh abundance, prevents visual cycle decline. This aim will test the extent that decreased Cfh generates inflammation from increased complement or MDA mediated cytokine expression to activate Stat3, which decreases visual cycle gene expression, function, and vision, and the impact of Ptx3 on Cfh abundance to regulate Cfh mediated inflammation. 2. Determine the extent that chronic oxidative stress impairs the visual cycle through Notch signaling. Oxidative stress activates Notch signaling, which can induce the transcription factor Sox9 to control the expression of a network of 6 visual cycle genes. While acute Notch signaling increases Sox9, chronic Notch signaling decreases Sox9. This aim will explore the extent that chronic oxidative stress activates Notch signaling, and how Notch influences visual cycle function through Sox9. 3. Determine the extent that CD46 regulates Notch signaling and Sox9 mediated visual cycle gene function. Besides its complement regulatory action, CD46 binds Jag1 to impede Notch signaling. Thus, decreased CD46 makes Jag1 available to activate Notch signaling as an alternative, non-complement function. This aim will explore the extent that decreased CD46 influences Notch signaling and visual cycle function through Jag1. Since CD46 is not expressed in somatic rodent cells, we will use iPS RPE cells with mutations in key CD46 domains to address this aim. These contributions are significant because if successful, novel pathways will be identified as targets to treat vision loss in AMD. The research is innovative since we will investigate understudied areas including mechanisms of vision loss from the synergistic impact of oxidative stress and innate immunity, the role of Stat3, Notch, and Sox9, and unconventional, non-complement functions of complement regulators on the visual cycle using unique, state-of-the-art genetic mice with fresh, but decisive factors that have not been previously tested. Targeted therapy that neutralizes pathways that degrade visual cycle gene expression, function, and vision from oxidative stress and overactive innate immunity is expected to result from this work.

项目概要 年龄相关性黄斑变性（AMD）是老年人失明的主要原因。目前，没有 治疗可以恢复任何形式的 AMD 的视力。为了解决这个缺点，本提案将重点关注 可以恢复视力的机制。视觉循环对 11-顺式视黄醛 (11-cRAL) 的再循环是 RPE 对视力至关重要的功能。虽然氧化应激和补体是 AMD 不可或缺的因素 病理生理学方面，它们对视觉周期的影响尚不清楚。该提案的目标是定义如何 氧化应激和先天免疫会损害视觉周期，从而降低 AMD 的视力。假设为 测试表明，氧化应激和补体调节因子 Cfh 和 CD46 受损会降低视觉周期 网络。拟议的具体目标是： 1. 确定氧化应激 i) 损害 Cfh 的程度，以诱导 炎症会降低视觉周期基因表达，ii) 诱导 Ptx3，并通过调节 Cfh 丰度，防止视觉周期衰退。该目标将测试 Cfh 降低产生的程度 补体或 MDA 介导的细胞因子表达增加而激活 Stat3 引起的炎症， 降低视觉周期基因表达、功能和视力，以及 Ptx3 对 Cfh 丰度的影响 调节 Cfh 介导的炎症。 2. 确定慢性氧化应激损害视力的程度 通过Notch信号循环。氧化应激激活Notch信号，从而诱导转录 Sox9 因子控制 6 个视觉周期基因网络的表达。虽然急性Notch信号传导 Sox9 增加，慢性 Notch 信号传导减少 Sox9。该目标将探讨慢性氧化的程度 压力激活 Notch 信号传导，以及 Notch 如何通过 Sox9 影响视觉周期功能。 3. 确定 CD46 调节 Notch 信号传导和 Sox9 介导的视觉周期基因功能的程度。除了它的 CD46 结合 Jag1 来阻碍 Notch 信号传导。因此，CD46 的减少使得 Jag1 可作为替代、非补充功能激活 Notch 信号。这一目标将探索 CD46 减少通过 Jag1 影响 Notch 信号传导和视觉周期功能。由于 CD46 是 啮齿动物体细胞中不表达，我们将使用关键 CD46 结构域发生突变的 iPS RPE 细胞来 解决这一目标。这些贡献意义重大，因为如果成功，新的途径将被确定为 治疗 AMD 视力丧失的目标。这项研究具有创新性，因为我们将调查尚未研究的领域 包括氧化应激和先天免疫的协同影响导致视力丧失的机制， Stat3、Notch 和 Sox9 的作用，以及补体调节因子的非常规、非补体功能 使用独特、最先进的基因小鼠进行视觉循环，这些小鼠具有新鲜但决定性的因素，这些因素尚未被研究过。 之前测试过。中和降低视觉周期基因表达途径的靶向治疗， 这项工作预计会产生氧化应激和过度活跃的先天免疫功能和视力。

项目成果

Cigarette Smoke Triggers Loss of Corneal Endothelial Cells and Disruption of Descemet's Membrane Proteins in Mice.

香烟烟雾会引发小鼠角膜内皮细胞的损失和后弹力层膜蛋白的破坏。

• 发表时间: 2021
• 影响因子: 4.4
• 作者: Ali, Muhammad;Khan, Shahid Y;Jang, Yura;Na, Chan Hyun;Talbot Jr, C Conover;Gottsch, John D;Handa, James T;Riazuddin, S Amer
• 通讯作者: Riazuddin, S Amer

Brolucizumab-associated intraocular inflammation in eyes without retinal vasculitis.

无视网膜血管炎的眼睛中 Brolucizumab 相关的眼内炎症。

• 发表时间: 2021-07
• 作者: Witkin, Andre J;Hahn, Paul;Murray, Timothy G;Arevalo, J Fernando;Blinder, Kevin J;Choudhry, Netan;Emerson, Geoff G;Goldberg, Roger A;Kim, Stephen J;Pearlman, Joel;Schneider, Eric W;Tabandeh, Homayoun;Wong, Robert W
• 通讯作者: Wong, Robert W

Retinal Anatomy and Electrode Array Position in Retinitis Pigmentosa Patients After Argus II Implantation: An International Study.

Argus II 植入后色素性视网膜炎患者的视网膜解剖结构和电极阵列位置：一项国际研究。

• DOI: 10.1016/j.ajo.2018.06.012
• 发表时间: 2018-09
• 期刊: American journal of ophthalmology
• 影响因子: 4.2
• 作者: Gregori NZ;Callaway NF;Hoeppner C;Yuan A;Rachitskaya A;Feuer W;Ameri H;Arevalo JF;Augustin AJ;Birch DG;Dagnelie G;Grisanti S;Davis JL;Hahn P;Handa JT;Ho AC;Huang SS;Humayun MS;Iezzi R Jr;Jayasundera KT;Kokame GT;Lam BL;Lim JI;Mandava N;Montezuma SR;Olmos de Koo L;Szurman P;Vajzovic L;Wiedemann P;Weiland J;Yan J;Zacks DN
• 通讯作者: Zacks DN

The impact of lipids, lipid oxidation, and inflammation on AMD, and the potential role of miRNAs on lipid metabolism in the RPE.

脂质、脂质氧化和炎症对 AMD 的影响，以及 miRNA 对 RPE 脂质代谢的潜在作用。

• 发表时间: 2019
• 影响因子: 3.4
• 作者: Jun, Sujung;Datta, Sayantan;Wang, Lei;Pegany, Roma;Cano, Marisol;Handa, James T
• 通讯作者: Handa, James T

Occlusive Retinal Vasculitis Following Intravitreal Brolucizumab.

玻璃体内注射 Brolucizumab 后发生闭塞性视网膜血管炎。

• 发表时间: 2020-07
• 作者: Witkin, Andre J;Hahn, Paul;Murray, Timothy G;Arevalo, J Fernando;Blinder, Kevin J;Choudhry, Netan;Emerson, Geoff G;Goldberg, Roger A;Kim, Stephen J;Pearlman, Joel;Schneider, Eric W;Tabandeh, Homayoun;Wong, Robert W
• 通讯作者: Wong, Robert W