Mitochondrial Dysfunction in a New Model of Dry AMD

新型干性 AMD 中的线粒体功能障碍

基本信息

批准号：
9333371
负责人：
SCOTT W COUSINS
金额：
$ 19.88万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9333371
关键词：
Actins Acute Affect Age related macular degeneration Aging Air Pollutants Biochemical Biological Biology Blindness Calcium Cell Culture Techniques Cells Chronic Collagen Complement Data Degenerative Disorder Deposition Developed Countries Developing Countries Diet Disease Dose Drug Targeting Drusen Elderly Environmental Risk Factor Exposure to Functional disorder Genetic Goals Health High Fat Diet Hydroquinones Hypoxia In Vitro Inflammation Inflammatory Injury Investigation Laboratories Legal Blindness Life Style Light Link Lipids MAP Kinase Gene MAPK14 gene Matrix Metalloproteinases Mediator of activation protein Mitochondria Modeling Morbidity - disease rate Mus Nurses Oxidants Pathogenesis Pathway interactions Peptides Pigment Epithelium Plasticizers Plastics Play Population Research Research Personnel Resources Retina Retinal Diseases Role Signal Pathway Signal Transduction Signaling Molecule Smog Stimulus Structure of retinal pigment epithelium Superoxides Therapeutic Time Toxic Environmental Substances United States Up-Regulation Vesicle Vimentin Visual aged apolipoprotein E-4 base cell injury cigarette smoking cigarette smoking clinically relevant cost cytokine effective therapy exhaust genetic manipulation geographic atrophy in vivo mitochondrial dysfunction mouse model new therapeutic target novel pollutant prevent response response to injury therapeutic target therapy development tobacco tar

项目摘要

PROJECT SUMMARY Nonexudative, or “dry,” age-related macular degeneration (AMD) is a major cause of visual morbidity, for which there are no effective treatments. Our laboratory has previously implicated the environmental toxicant hydroquinone (HQ), which is found in cigarette smoke, pollutants, and plastics, as a potential cause of dry AMD. We have shown that aged mice fed a diet with low-dose HQ develop AMD-like sub-retinal pigment epithelium (RPE) deposits. Additionally, exposure of cultured RPE cells to HQ triggers numerous nonlethal injury responses (cytoskeletal disruption, cell “blebbing”, increased collagen synthesis, etc.) via activation of specific cytoplasmic signaling cascades (i.e. ASK1, p38 MAPK, pHSP25, others). Based on our preliminary studies, we propose the conceptual hypothesis that HQ and other AMD-relevant triggers promote subRPE deposit formation via induction of mitochondrial dysfunction. Linking in vitro observations of RPE cell culture to in vivo RPE biology has proven quite challenging because existing mouse models of subRPE deposits require aging, genetic manipulations, high-fat diet, or other injury (i.e. blue light, complement, etc.). Since these models are time-, cost-, and resource-intensive, they do not lend themselves to in-depth mechanistic studies to characterize the pathobiology of subRPE deposit formation. The purpose of this R21 proposal is to support exploratory studies of a novel mouse model for acute subRPE deposit formation, induced by subconjunctival exposure to HQ in young mice over a two-week period, (1) to show that these deposits are precursors of deposits in chronic models in aged mice; and (2) to characterize relevant biochemical mechanisms of deposit formation. Specifically, we seek to demonstrate the central role of mitochondrial dysfunction in triggering cytoplasmic signaling pathways that regulate subRPE deposit biology in vivo. Second, we desire to evaluate the ApoE4 lipid dysregulation model of subRPE deposits to assess biologic overlap between the ApoE4 deposit model and the acute periocular HQ model. Finally, this project will introduce a novel mitochondria-targeting peptide, MTP-131, to determine whether treatment of mitochondrial dysfunction can mitigate RPE cellular injury, and prevent and perhaps regress subRPE deposits. Positive findings in support of our conceptual hypothesis would validate mitochondrial dysfunction as a novel therapeutic target for dry AMD.

项目概要非渗出性或“干性”年龄相关性黄斑变性 (AMD) 是视力下降的主要原因发病率，我们的实验室之前没有发现有效的治疗方法。环境毒物氢醌 (HQ)，存在于香烟烟雾、污染物、和塑料，作为干性 AMD 的潜在原因我们已经证明，老年人给小鼠喂食含低剂量 HQ 会形成类似 AMD 的视网膜下色素上皮 (RPE) 沉积物。将培养的 RPE 细胞暴露于 HQ 会引发许多非致命性损伤反应（细胞骨架破坏、细胞“起泡”、胶原蛋白合成增加等）特定的细胞质信号级联（即 ASK1、p38 MAPK、pHSP25 等）。初步研究中，我们提出了 HQ 和其他 AMD 相关的概念假设触发器通过诱导线粒体功能障碍促进 subRPE 沉积物的形成。 RPE 细胞培养的体外观察与体内 RPE 生物学的联系已得到充分证明具有挑战性，因为现有的 subRPE 沉积小鼠模型需要老化、遗传操作、高脂肪饮食或其他损伤（即蓝光、补体等）。模型是时间、成本和资源密集型的，它们不适合深入研究机制研究来表征 subRPE 沉积物形成的病理学特征。 R21 提案的目的是支持新型小鼠模型的探索性研究幼鼠结膜下暴露于 HQ 诱导急性 subRPE 沉积物形成在两周内，（1）表明这些沉积物是慢性沉积物的前体老年小鼠模型；(2) 表征沉积物的相关生化机制具体来说，我们试图证明线粒体功能障碍在形成中的核心作用。触发调节体内 subRPE 沉积生物学的细胞质信号传导途径。我们希望评估 subRPE 沉积物的 ApoE4 脂质失调模型来评估 ApoE4 沉积模型和急性眼周 HQ 模型之间的生物学重叠。该项目将引入一种新型线粒体靶向肽 MTP-131，以确定线粒体功能障碍的治疗是否可以减轻 RPE 细胞损伤并预防或许还有回归 subRPE 存款的积极结果支持我们的概念。该假设将验证线粒体功能障碍作为干性 AMD 的新治疗靶点。