Blood outer retina barrier regulation

血液外视网膜屏障调节

基本信息

批准号：
10329927
负责人：
DOUGLAS Chase DEAN
金额：
$ 57.74万
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/10329927
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 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.

项目概要/摘要视网膜色素变性（RP）中杆状光感受器特异性基因的突变导致视网膜色素变性减少周边视力和夜间视力。但是，这是锥体功能的继发性丧失，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力下降最使人衰弱的任务。导致 RP 视锥细胞功能丧失的事件仍在处理中解开。与其他神经元一样，光感受器依赖于葡萄糖，它们利用葡萄糖来能量以及持续合成以取代富含视觉色素的膜外层节段（OS），因为它们每天都会经历光诱导的吞噬作用。 RPE 充当血液-外视网膜屏障从脉络膜循环输送葡萄糖和营养物质到邻近的感光器。我们提供的证据表明葡萄糖从 RPE 转运至新操作系统合成的光感受器与操作系统吞噬作用有关。作为丰富的突变体 RP 中杆 OS 丢失且吞噬作用减弱，葡萄糖转运变短循环导致视锥细胞饥饿。我们将检查信号通路的调节 RPE 的葡萄糖转运以及相关的代谢组/表观基因组变化小鼠和猪的 RP 进展过程中的细胞，这是 RP 的大型动物模型，其中视锥细胞集中形成视觉条纹。