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Blood outer retina barrier regulation

血液外视网膜屏障调节

基本信息

批准号：
10093049
负责人：
DOUGLAS Chase DEAN
金额：
$ 57.63万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
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/10093049
关键词：
Adaptor Signaling Protein Age Animal Model Apical Arrestins Automobile Driving Back Binding Birth Blood Blood Circulation Cell Death Cells Choroid Clathrin Complex Cone Cytoplasm Cytoskeletal Modeling DNA Dark Adaptation Development Disease Disease Progression Down-Regulation Endocytosis Environment Epigenetic Process Epithelial Cells Event Face Family Family suidae Feedback Feeds GLUT 4 protein Gene Expression Genes Glucose Glucose Transporter Hypoglycemia Injections Insulin Integrins Investigation Label Light Link Lipids Malignant Neoplasms Mass Spectrum Analysis Metabolic Metabolic Pathway Metabolism Modeling Mus Mutation Neurons Nutrient Pathway interactions Peripheral Phagocytosis 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 TXNIP gene Time Transplantation Vision Visual Work alpha ketoglutarate coated pit cofactor epigenome experimental study functional loss glucose metabolism glucose transport glucose uptake histone demethylase inhibitor/antagonist loss of function macrophage metabolome mutant overexpression prevent receptor recruit response restoration retinal rods scaffold subretinal injection uptake

项目摘要

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。