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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）：青光眼等神经退行性眼病导致美国大量人口失明，但缺乏有效的治疗方法。该项目的最终目标是通过利用一种独特的内源性神经保护剂——β1R伴侣，开发拯救视网膜神经变性的新方法，其抗凋亡特性正在被发现。我们的体内研究表明？ 1R 具有 ROS（活性氧）抑制作用，可防止神经节细胞和感光细胞中的视网膜变性。该项目是第一项测试功效的研究这？ 1R 介导的视网膜神经保护作用？ 1R 基因治疗，通过过度表达 ?干细胞来源的光感受器中存在1R，以增强其移植后的存活率，并通过使用sigma-1受体敲除模型（?1ko）与慢性DBA/2J青光眼模型或rd10模型相结合。在具体目标 1 中，我们将研究缺少 ? 的影响。 1R 分别表示青光眼 DBA/2J 模型和 RP rd10 模型中神经节细胞和感光细胞的体内活力。自从我们发现神经节细胞？在急性模型中，1ko 小鼠比野生型小鼠更容易受到视网膜变性的影响，我们将使用与 ? 杂交的新模型进一步测试我们的发现。 1ko和DBA/2J的慢性青光眼模型。我们还将进一步研究 ? 的神经保护作用。视网膜感光细胞中的 1R 尚未定义，在我们通过交叉 ¿1ko 和 rd10 生成的新模型中。将比较存在和不存在 ? 的情况下的视网膜 ROS 水平。这些型号中的 1R。在具体目标 2 中，我们将测试 ?使用慢病毒挽救视网膜变性的 1R 基因疗法。增加 ? 1R 丰度在视网膜中，我们将用携带 ? 的慢病毒转导 rd10 小鼠光感受器。 1R 基因和视蛋白启动子采用视网膜下注射技术。过度表达 ? 的转基因眼的视网膜功能1R 将与注入 ? 的进行比较1R 阴性模拟病毒。在具体目标 3 中，我们将探讨 ? 的神经保护作用。 1R 对干细胞来源的光感受器移植后存活的影响。在干细胞治疗中，由于视杆细胞死亡而导致氧化应激升高，视杆细胞是视网膜中氧气的主要消耗者，对移植的光感受器的存活造成有害威胁。我们会过度表达？人类胚胎干细胞衍生的光感受器中的 1R 可提高其移植到 rd10 视网膜后的存活率。的促生存效应？将与用 ? 转导的对照移植细胞相比，评估移植的光感受器上的 1R。 1R 阴性模拟病毒。最终，我们的发现将带来新的？ 1R 靶向治疗策略可挽救毁灭性的视网膜神经退行性疾病。