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

测试葡萄糖剥夺在色素性视网膜炎继发性视锥细胞死亡过程中的作用

基本信息

批准号：
9919561
负责人：
Claudio Punzo
金额：
$ 20.94万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919561
关键词：
Aerobic Affect Affinity Alleles Anabolism Animal Model Biological Birth Blindness Candidate Disease Gene Cells Cellular Metabolic Process Cessation of life Color Complete Blindness Complex Cone Data Dependence Disease Ensure Event FRAP1 gene Family suidae Foundations Funding Gene Expression Gene Transfer Genes Glucose Glucose Transporter Grant Hexokinase 2 Histidine Human Individual Inherited Injections Knock-out Mediating Metabolic Metabolism Modeling Mus Mutation Neurons Night Blindness Nutrient Nutritional Pathologic Pathway interactions Phosphotransferases Photoreceptors Play Process Proline Publications Recombinants Research Research Personnel Retina Retinal Cone Retinal Degeneration Retinitis Pigmentosa Rhodopsin Rod Role SLC2A1 gene Structure of retinal pigment epithelium Testing Therapeutic Therapeutic Intervention Therapeutic Uses Time Tuberous sclerosis protein complex Viral Vision Work adeno-associated viral vector base deprivation design disease-causing mutation experimental study gene therapy glucose metabolism glucose uptake improved mouse model photoreceptor degeneration retinal rods rho uptake

项目摘要

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.

PI：克劳迪奥·庞佐项目概要人和小鼠的视杆细胞和视锥细胞光感受器之间的神经元间关系是这样的：死亡总是导致锥体死亡；然而，视锥细胞的损失对视杆细胞没有影响。这种现象起到了在遗传性视网膜退行性疾病色素性视网膜炎中发挥重要作用，作为大多数致病原因鉴定出的等位基因编码专门在杆状细胞中表达的基因。因为视锥细胞对于人类来说是必不可少的视力，正是它们的丧失导致失明。我们最近提出视锥细胞死亡是细胞自主的事件由营养吸收减少引起，特别是葡萄糖，并表明细胞自主激活雷帕霉素复合物 1 (mTORC1) 的哺乳动物靶标激酶，通过删除其负调节因子结节性硬化症复合蛋白 1 (TSC1) 可显着延长视锥细胞存活时间。自从我们最初的发现以来其他人也支持这样的观点，即色素性视网膜炎中的继发性视锥细胞死亡主要是由以下原因引起的：视锥细胞中葡萄糖不足。我们的细胞自主激活视锥细胞中的 mTORC1，通过以下方式促进视锥细胞存活：改善以下 3 个葡萄糖相关过程：摄取、保留和代谢。在这笔赠款中，我们希望测试这 3 个过程中的每一个对视锥细胞存活的贡献程度。我们已经鉴定出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之一。这里我们建议测试一下通过 rAAV 介导的基因转移到视锥细胞，每个基因对视锥细胞存活的贡献有多大。我们将测试每个基因单独介导的锥体生存效应以及同时两个基因组合介导的锥体生存效应。到确保我们的方法与突变无关，我们将在两种小鼠模型中进行实验视网膜色素变性。所提出的研究的完成将为设计一个延长患有色素性视网膜炎的人类视力的合理治疗方法。