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.

项目摘要/摘要视网膜炎色素（RP）中杆感光特异性基因的突变导致降低外围和夜间视觉。但是，这是圆锥功能的次要丧失，导致降低用于阅读，面部识别和其他每日其他日光的高分辨率日光视野最令人衰弱的任务。导致RP中锥功能丧失的事件仍在解开。像其他神经元一样，感光体依赖于葡萄糖，它们用于能量以及持续的合成以取代富含视觉色素的膜外部段（OS）每天都会发生光诱导的吞噬作用。 RPE用作脉络膜循环中传输葡萄糖和营养的血液驱动视网膜屏障到相邻的光感受器。我们提供的证据表明葡萄糖从RPE转运到新OS合成的感光体与OS吞噬作用有关。作为丰富的突变体 ROD OS丢失，RP的吞噬作用减少，葡萄糖转运变短 - 引起锥饥饿的循环。我们将检查调节的信号通路从RPE和连接的代谢组/表观基因组变化的葡萄糖转运小鼠和猪的RP进展过程中的细胞，这是RP的大动物模型锥体集中在视觉上。