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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：
9513208
负责人：
Lianwang Guo
金额：
$ 16.5万
依托单位：
OHIO STATE UNIVERSITY
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9513208
关键词：
Sigma Chaperone Mediated vivo Neuroprotection

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 σ1R chaperone, whose anti-apoptotic properties are being uncovered. Our in vivo studies suggest that the σ1R 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 σ1R-mediated retinal neuroprotection by σ1R gene therapy, by overexpressing the σ1R in stem cell-derived photoreceptors to enhance their post-transplantation survival, and by using the sigma-1 receptor knock model (σ1ko) 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 σ1R 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 σ1ko 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 σ1ko and the chronic glaucoma model of DBA/2J. We will also extend our investigation into a neuroprotective role of the σ1R in retinal photoreceptors, which has yet to be defined, in a new model that we have generated by crossing σ1ko and rd10. Retinal ROS levels will be compared in the presence and absence of the σ1R in these models. In Specific Aim 2, we will test σ1R gene therapy for rescue of retinal degeneration using lentiviruses. To increase the σ1R abundance in the retina, we will transduce the rd10 mouse photoreceptors with lentiviruses harboring the σ1R gene and the Opsin promoter using a technique of subretinal injection. Retinal functions of the transgenic eye overexpressing the σ1R will be compared to that injected with the σ1R-negative mock virus. In Specific Aim 3, we will explore the neuroprotective effect of the σ1R 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 σ1R in human embryonic stem cell-derived photoreceptors to enhance their survival after transplantation into the rd10 retina. The pro-survival effect of the σ1R on transplanted photoreceptors will be assessed in comparison to the control transplant cells that are transduced with the σ1R-negative mock virus. Ultimately, our finding will lead to new σ1R-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独特的内源性神经保护剂 σ1R 伴侣来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，σ1R 具有 ROS（活性氧）抑制作用，并且可以防止神经节细胞和感光细胞中的视网膜变性。该项目代表了第一项通过σ1R基因疗法测试σ1R介导的视网膜神经保护功效的研究，通过在干细胞来源的光感受器中过度表达σ1R以提高其移植后存活率，并使用sigma-1受体敲除模型（σ1ko）与慢性DBA/2J青光眼模型或rd10模型相结合。在具体目标 1 中，我们将分别在青光眼 DBA/2J 模型和 RP rd10 模型中检查 σ1R 缺失对体内神经节细胞和感光细胞活力的影响。由于我们发现在急性模型中，σ1ko 小鼠的神经节细胞比野生型小鼠更容易发生视网膜变性，因此我们将使用与 σ1ko 和 DBA/2J 慢性青光眼模型杂交的新模型进一步测试我们的发现。我们还将在通过交叉 σ1ko 和 rd10 生成的新模型中扩展对 σ1R 在视网膜光感受器中的神经保护作用的研究，该作用尚未定义。将比较这些模型中存在和不存在 σ1R 时的视网膜 ROS 水平。在具体目标 2 中，我们将测试 σ1R 基因疗法使用慢病毒拯救视网膜变性的效果。为了增加视网膜中 σ1R 的丰度，我们将使用视网膜下注射技术，用含有 σ1R 基因和视蛋白启动子的慢病毒转导 rd10 小鼠光感受器。过表达 σ1R 的转基因眼的视网膜功能将与注射 σ1R 阴性模拟病毒的视网膜功能进行比较。在具体目标 3 中，我们将探讨 σ1R 对干细胞来源的光感受器移植后存活的神经保护作用。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。我们将在人类胚胎干细胞衍生的光感受器中过度表达 σ1R，以提高其移植到 rd10 视网膜后的存活率。将与用 σ1R 阴性模拟病毒转导的对照移植细胞进行比较，评估 σ1R 对移植光感受器的促生存作用。最终，我们的发现将带来新的 σ1R 靶向治疗策略，以拯救毁灭性的视网膜神经退行性疾病。