Testing the role of Glucose deprivation during secondary cone death in Retinitis Pigmentosa

少年派：克劳迪奥·庞佐 项目摘要 人和小鼠视杆细胞和视锥细胞感受器之间的神经元间关系是这样的 死亡总是会导致锥体死亡；然而，锥体的丧失对杆状细胞没有影响。这种现象起到了一种 在遗传性视网膜退行性疾病视网膜色素变性中的重要作用，作为大多数疾病的致病因素 识别出的等位基因编码的基因只在杆状细胞中表达。因为锥体对人类来说是必不可少的 视力，正是他们的失落导致了失明。我们最近提出锥体死亡是一种细胞自主性 由营养摄取减少引起的事件，特别是葡萄糖，并表明细胞自主激活 雷帕霉素复合体1的哺乳动物靶蛋白(MTORC1)，通过缺失其负调控因子 结节性硬化症复合蛋白1(TSC1)，显著延长视锥细胞存活时间。因为我们最初的发现 其他人也支持视网膜色素变性继发性视锥细胞死亡主要是由 球果中的葡萄糖不足。我们的细胞自主激活锥体中的mTORC1通过以下方式促进锥体存活 改善以下3个与葡萄糖相关的过程：摄取、滞留和代谢。在这笔赠款中，我们希望 为了测试这三个过程中的每一个对锥体存活的贡献程度。我们已经确定了3个基因， 通过对我们的数据进行理性分析，每个数据代表这三个过程中的一个。在这里，我们建议测试 通过rAAV介导的视锥细胞基因转移，每个基因对视锥细胞存活的贡献有多少。我们将测试 球果存活效应由每个基因单独介导，同时由两个基因联合作用。至 为了确保我们的方法是突变独立的，我们将在两个小鼠模型上进行实验 视网膜色素变性。拟议研究的完成将为设计一种 合理的治疗方法延长人类视网膜色素变性患者的视力。

PI: Claudio Punzo Project Summary The inter-neuronal relationship between rod and cone photoreceptors in human and mouse is such that rod death always leads to cone death; however, loss of cones has no effect on rods. This phenomenon plays an important role in the inherited retinal degenerative disease retinitis pigmentosa, as most disease-causing alleles identified encode for genes that are exclusively expressed in rods. Since cones are essential for human vision, it is their loss that leads to blindness. We have recently proposed that cone death is a cell autonomous event caused by reduced nutrient uptake, in particular glucose, and showed that cell autonomous activation of the kinase mammalian target of rapamycin complex 1 (mTORC1), by deletion of its negative regulator the tuberous sclerosis complex protein 1 (TSC1), significantly prolongs cone survival. Since our initial findings others have also supported the notion that secondary cone death in retinitis pigmentosa is manly caused by a shortage of glucose in cones. Our cell autonomous activation of mTORC1 in cones promoted cone survival by improving the following 3 glucose related processes: uptake, retention and metabolism. In this grant we want to test to which extent each of these 3 processes contributes to cone survival. We have identified 3 genes, through a rational analysis of our data, each representing one of these 3 processes. Here we propose to test how much each gene contributes to cone survival by rAAV mediated gene transfer to cones. We will test the cone survival effect mediated by each gene individually and in combination of two genes at the same time. To ensure that our approach is mutation independent we will carry out our experiments in two mouse models of retinitis pigmentosa. Accomplishment of the proposed research will lay the foundation for the design of a rational therapeutic approach to extend vision in humans with retinitis pigmentosa.