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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