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Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina

Sigma-1 伴侣介导的体内视网膜神经保护

基本信息

批准号：
8523895
负责人：
Lianwang Guo
金额：
$ 31.96万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523895
关键词：
Acute Apoptosis Apoptotic Blindness Cell Death Cell Transplants Cells Cessation of life Characteristics Chronic Data Degenerative Disorder Disease model Environment Event Exposure to Eye Eye diseases Genes Glaucoma Goals Human Investigation Knock-out Lead Light Mediating Membrane Proteins Methods Modeling Molecular Chaperones Morphology Mus Mutation Nerve Crush Nerve Degeneration Neurodegenerative Disorders Neuroprotective Agents Opsin Optic Nerve Oxidative Stress Oxygen Photoreceptors Population Process Property Proteins Reactive Oxygen Species Reporting Retina Retinal Retinal Degeneration Retinal Ganglion Cells Retinal Photoreceptors Retinitis Pigmentosa Role Stem cells Subfamily lentivirinae Techniques Testing Therapeutic Transgenic Organisms Transplantation Viral Vector Virus Vision cellular transduction effective therapy efficacy testing ganglion cell gene therapy human embryonic stem cell in vivo mouse model neuroprotection new therapeutic target novel overexpression promoter protective effect receptor retinal rods sigma-1 receptor stem cell therapy subretinal injection therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Neurodegenerative eye diseases such as glaucoma cause blindness in a large population in the USA, yet effective treatments are lacking. The ultimate goal of this project is to develop new methods for rescue of retinal neurodegeneration by exploiting a unique endogenous neuroprotective agent, the ?1R chaperone, whose anti-apoptotic properties are being uncovered. Our in vivo studies suggest that the ? 1R is ROS (reactive oxygen species)-suppressing and is protective against retinal degeneration in ganglion cells as well as in photoreceptors. This project represents the first study to test the efficacy of the ? 1R-mediated retinal neuroprotection by ? 1R gene therapy, by overexpressing the ? 1R in stem cell-derived photoreceptors to enhance their post-transplantation survival, and by using the sigma-1 receptor knock model (? 1ko) combined with the chronic DBA/2J glaucoma model or rd10 model. In Specific Aim 1, we will examine the impact of the absence of the ? 1R for the viability of ganglion cells and photoreceptors in vivo in the DBA/2J model of glaucoma and the rd10 model of RP, respectively. Since we have discovered that ganglion cells of the ? 1ko mice are more susceptible to retinal degeneration than the wild type in an acute model, we will further test our finding using a new model crossed with the ? 1ko and the chronic glaucoma model of DBA/2J. We will also extend our investigation into a neuroprotective role of the ? 1R in retinal photoreceptors, which has yet to be defined, in a new model that we have generated by crossing ¿1ko and rd10. Retinal ROS levels will be compared in the presence and absence of the ? 1R in these models. In Specific Aim 2, we will test ? 1R gene therapy for rescue of retinal degeneration using lentiviruses. To increase the ? 1R abundance in the retina, we will transduce the rd10 mouse photoreceptors with lentiviruses harboring the ? 1R gene and the Opsin promoter using a technique of subretinal injection. Retinal functions of the transgenic eye overexpressing the ? 1R will be compared to that injected with the ? 1R-negative mock virus. In Specific Aim 3, we will explore the neuroprotective effect of the ? 1R on the post-transplantation survival of stem cell-derived photoreceptors. In stem cell therapy, elevated oxidative stress due to the death of rods, which are active major consumers of oxygen in the retina, imposes detrimental threat to the survival of transplanted photoreceptors. We will overexpress the ? 1R in human embryonic stem cell-derived photoreceptors to enhance their survival after transplantation into the rd10 retina. The pro-survival effect of the ? 1R on transplanted photoreceptors will be assessed in comparison to the control transplant cells that are transduced with the ? 1R-negative mock virus. Ultimately, our finding will lead to new ? 1R-targeted therapeutic strategies for rescue of the devastating retinal neurodegenerative diseases.

描述（由申请人提供）：神经退行性眼病（如青光眼）在美国造成大量人群失明，但缺乏有效的治疗方法。本项目的最终目标是开发新的方法，通过利用一种独特的内源性神经保护剂，视网膜神经变性的救援？1 R分子伴侣，其抗凋亡特性正在被发现。我们的体内研究表明，？IR是ROS（活性氧）抑制，并保护神经节细胞以及光感受器中的视网膜变性。该项目代表了第一项测试的？1 R介导的视网膜神经保护作用？1 R基因治疗，通过过度表达？1 R的干细胞衍生的光感受器，以提高其移植后的生存，并通过使用西格玛-1受体敲模型（？1 ko）联合慢性DBA/2 J青光眼模型或rd 10模型。在具体目标1，我们将研究的影响，没有？1 R分别用于青光眼的DBA/2 J模型和RP的rd 10模型中的体内神经节细胞和光感受器的活力。因为我们已经发现，神经节细胞的？在急性模型中，1 ko小鼠比野生型小鼠更容易发生视网膜变性，我们将使用与1 ko小鼠杂交的新模型进一步测试我们的发现。1 ko和DBA/2 J慢性青光眼模型。我们还将扩大我们的调查到神经保护作用的？视网膜光感受器中的1 R，尚未定义，在我们通过交叉<$1ko和rd 10生成的新模型中。视网膜活性氧水平将进行比较，在存在和不存在的？1 R在这些模型中。在具体目标2中，我们将测试？使用慢病毒的1 R基因治疗用于拯救视网膜变性。为了增加？1 R丰度的视网膜，我们将deletion的rd 10小鼠光感受器与慢病毒窝藏？1 R基因和视蛋白启动子。视网膜功能的转基因眼睛过度表达？1 R将与注射？1 R阴性模拟病毒。在具体目标3，我们将探讨神经保护作用的？1 R对干细胞衍生的光感受器的移植后存活的影响。在干细胞治疗中，由于视杆细胞死亡而引起的氧化应激升高，视杆细胞是视网膜中氧的活跃主要消耗者，对移植的光感受器的存活造成有害的威胁。我们会过度表达？1 R在人胚胎干细胞衍生的光感受器中的作用，以提高其移植到rd 10视网膜后的存活率。的亲生存效果？1 R对移植的光感受器将进行评估相比，对照移植细胞转导？1 R阴性模拟病毒。最终，我们的发现将导致新的？1 R靶向治疗策略用于挽救毁灭性的视网膜神经退行性疾病。