Flavoprotein Autofluorescence Imaging in AMD

AMD 中的黄素蛋白自发荧光成像

基本信息

批准号：
8953161
负责人：
SCOTT W COUSINS
金额：
$ 20.64万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2017-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8953161
关键词：
Acute Affect Age related macular degeneration Aging Algorithms Animals Biological Markers Bruch&apos s basal membrane structure Cell Culture Techniques Cells Cessation of life Characteristics Chronic Cicatrix Clinic Clinical Clinical Research Companions Computer software Coupled Cultured Cells Cytosol Deposition Developed Countries Devices Disease Disease model Drug Targeting Drusen Elderly Electron Transport Experimental Animal Model Exposure to Extracellular Matrix Exudative age-related macular degeneration Eye Flavoproteins Fluorescence Spectroscopy Frequencies Functional disorder Genetic Goals Health Hemorrhage Histopathology Human Hydroquinones Image Imaging Device Individual Induced Mutation Injection of therapeutic agent Lasers Legal Blindness Life Lipids Lipofuscin Measures Mediating Metabolism Methods Mitochondria Mitochondrial DNA Mus Ophthalmoscopes Ophthalmoscopy Optics Oxidants Oxidases Oxidative Phosphorylation Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phospholipids Photoreceptors Pigment Epithelium of Eye Pilot Projects Plasma Population Production Proteomics Reperfusion Injury Research Retina Retinal Retinal Diseases Role Scanning Societies Source Staging Structure of retinal pigment epithelium Superoxides System Technology Therapeutic Time Tissues Toxic Environmental Substances United States Vascular Endothelial Growth Factors Work absorption age related base clinical application design effective therapy extracellular geographic atrophy human subject hydroquinone image processing imaging biomarker improved in vivo mitochondrial dysfunction mouse model novel optical spectra pre-clinical programs protein expression prototype public health relevance repaired response to injury

项目摘要

DESCRIPTION (provided by applicant): In developed societies, age-related macular degeneration (AMD) is the most common cause of legal blindness in people over age 65. Emerging evidence demonstrates an important role for retinal pigment epithelium (RPE) mitochondrial dysfunction in dry AMD pathobiology. Mitochondrial dysfunction is characterized by chronic overproduction of superoxide and diminished production of ATP, and it promotes activation of injury response pathways in RPE cells, leading to sub-RPE deposit formation (precursors of lipid-rich drusen) and dysregulation of extracellular matrix turnover, the hallmark features of dry AMD. Thus, mitochondrial-targeting drugs are emerging as an attractive class of potential therapeutics for dry AMD. Technologies to identify the presence of RPE mitochondrial dysfunction in living eyes are limited. Detecting mitochondrial dysfunction in vivo would enable selection of individuals who might benefit from mitochondria-targeting drugs and would accelerate mechanistic studies of mitochondrial dysfunction in dry AMD disease models. The goal of this project is to develop RPE flavoprotein autofluorescence as an imaging biomarker for mitochondrial dysfunction. Mitochondrial dysfunction is accompanied by an increased ratio in the oxidized to reduced forms of flavoproteins (especially FAD+), which are important components of the electron transport chain for ATP production. Increase in oxidized flavoprotein produces a characteristic shift in the autofluorescence emission spectra, which is easily measured in isolated cells or tissues. However, detecting this shift noninvasively in tissues of living animals or humans, especially the eye, is much more challenging. It requires both a specialized device to image the RPE and an analytical approach to detect the specific autofluorescence signature attributable to flavoprotein. In this project, we will design and build prototype multispectral imaging device using a rapidly tunable excitation laser source, an acousto-optical tunable barrier filter, and a confocal scanning laser ophthalmoscope retinal imager, integrated with analytical software based on synchronous fluorescence spectroscopy, to detect and quantify RPE flavoprotein autofluorescence. We will use cell culture and animal model experimental systems to develop and validate this technology, and we will adapt the integrated multispectral imaging device to initiate a pilot clinical study of RPE flavoprotein autofluorescence in human subjects without retinal disease and in subjects with AMD.

描述（由适用提供）：在发达的社会中，与年龄相关的黄斑变性（AMD）是65岁以上人群的法律失明的最常见原因。新兴证据表明，视网膜色素上皮（RPE）线粒体功能障碍在干燥AMD病理生物学中起着重要作用。线粒体功能障碍的特征是超氧化物的慢性产生和ATP的产生减少，并且促进了RPE细胞中损伤反应途径的激活，导致子RPE沉积物形成（脂质富含富含脂质的龙的前体）和细胞外基质失误的失调，并具有干燥的基质流失，Dry Amd的Hallmark特征。这就是线粒体靶向药物正在成为一种有吸引力的干室疗法类别。在活眼睛中识别RPE线粒体功能障碍的技术是有限的。在体内检测线粒体功能障碍将使可以选择可能从靶向线粒体靶向药物中受益的个体，并将加速干燥AMD疾病模型中线粒体功能障碍的机理研究。该项目的目的是开发RPE黄蛋白自动荧光作为线粒体功能障碍的成像生物标志物。线粒体功能障碍是通过氧化与还原形式的黄素蛋白（尤其是FAD+）的比例增加的，这是电子传输链的重要组成部分，以产生ATP的产生。氧化的黄素蛋白的增加会在自动荧光发射光谱中产生特征转移，该光谱很容易在分离的细胞或组织中测量。但是，在活动物或人类（尤其是眼睛）的组织中无创的这种转变是更大的挑战。它既需要一个专门的设备来对RPE进行成像，也需要一种分析方法来检测归因于黄蛋白的特定自动荧光特征。在这个项目中，我们将使用快速调谐激光源设计和构建原型多光谱成像设备，一个仿光光学的可调屏障过滤器以及共聚焦扫描激光视网膜视网膜成像仪，与基于同步荧光光谱和量化flavuere rpe的分析软件集成，并与分析软件集成。我们将使用细胞培养和动物模型实验系统来开发和验证这项技术，并将适应综合的多光谱成像装置，以启动无残留疾病和AMD受试者的人类受试者的RPE氟蛋白自动荧光的临床研究。