Blood outer retina barrier regulation

血液外视网膜屏障调节

• 批准号: 10561694
• 负责人: DOUGLAS Chase DEAN
• 金额: $ 59.6万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561694
• 关键词: AKT inhibition; Adaptor Signaling Protein; Age; Animal Model; Apical; Arrestins; Automobile Driving; Back; Binding; Birth; Blood; Catheters; Cell Death; Cells; Choroid; Circulation; Clathrin; Complex; Cone; Cytoplasm; Cytoskeletal Modeling; DNA; Dark Adaptation; Development; Disease Progression; Down-Regulation; Endocytosis; Environment; Epigenetic Process; Epithelial Cells; Event; Face; Family; Family suidae; Feedback; Feeds; GLUT 4 protein; GLUT-1 protein; Gene Expression; Genes; Glucose; Glucose Transport Induction; Glucose Transporter; Hypoglycemia; Injections; Insulin; Integrins; Investigation; Label; Light; Link; Lipids; Macrophage; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Modeling; Mus; Mutation; Neurons; Nutrient; Pathway interactions; Peripheral; Phagocytosis; Phagocytosis Induction; Phosphatidylserines; Phosphorylation; Photoreceptors; Proteins; Reading; Regulation; Resolution; Retina; Retinal Pigments; Retinitis Pigmentosa; Rod; Rod Outer Segments; Signal Pathway; Signal Transduction; Starvation; Structure of retinal pigment epithelium; Surface; Transplantation; Vision; Visual; Work; alpha ketoglutarate; blood glucose regulation; coated pit; cofactor; enhancing factor; epigenome; experimental study; functional loss; glucose metabolism; glucose transport; glucose uptake; histone demethylase; inhibitor; loss of function; metabolome; mutant; overexpression; prevent; receptor; recruit; response; restoration; retinal rods; scaffold; subretinal injection; uptake

Project Summary/Abstract Mutations in rod photoreceptor-specific genes in retinitis pigmentosa (RP) cause diminished peripherial and night-time vision. But, it is secondary loss of cone function, leading to diminished high-resolution daylight vision utilized for reading, facial recognition and other daily tasks that is most debilitating. Events leading to loss of cone function in RP are still being unraveled. Like other neurons, photoreceptors depend upon glucose, which they use for energy as well as ongoing synthesis to replace visual pigment-rich membraneous outer segments (OS) as they undergo daily light-induced phagocytosis. The RPE serves as a blood-outer retinal barrier transporting glucose and nutrients from the choroid circulation to adjacent photoreceptors. We provide evidence that glucose transport from the RPE to photoreceptors for new OS synthesis is linked to OS phagocytosis. As abundant mutant rod OS are lost and phagocytosis diminishes in RP, glucose transport becomes short- circuited leading to cone starvation. We will examine the signaling pathway regulating glucose transport from the RPE and linked metabolome/epigenome changes in these cells during RP progression in both mice and pigs, a large animal model of RP where cones are concentrated into a visual streak.

项目总结/摘要 视网膜色素变性（RP）中视杆细胞感光器特异性基因的突变导致视网膜色素变性的减少。 周边和夜间视觉。但是，这是锥功能的二次丧失，导致 用于阅读、面部识别和其他日常活动的高分辨率日光视觉减弱 这是最令人沮丧的任务。导致RP中锥体功能丧失的事件仍在研究中。 解开了像其他神经元一样，光感受器依赖于葡萄糖，它们用于 能量以及正在进行的合成，以取代视觉色素丰富的膜外 节（OS），因为它们每天经历光诱导的吞噬作用。RPE作为 从脉络膜循环转运葡萄糖和营养物的血液-视网膜外屏障 邻近的感光细胞。我们提供的证据表明，葡萄糖从RPE转运到 用于新OS合成的光受体与OS吞噬作用有关。作为丰富的突变体 RP中杆OS丢失，吞噬作用减少，葡萄糖转运变短- 导致球果饥饿。我们将研究信号通路调节 葡萄糖转运从RPE和相关的代谢组/表观基因组的变化，在这些 在小鼠和猪的RP进展过程中， 视锥细胞集中成视觉条纹。