Theranostics of Photoreceptor-RPE-Choroid Neurovascular Unit in Mouse Models of Eye Diseases

小鼠眼病模型中光感受器-RPE-脉络膜神经血管单元的治疗诊断

基本信息

批准号：
10090599
负责人：
Robert J Zawadzki
金额：
$ 33.78万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090599
关键词：
11 cis Retinal Affect Age Age related macular degeneration Aging Animal Model Animals Basement membrane Biochemical Biological Assay Blood Circulation Blood Vessels Blood flow Blood-Retinal Barrier Bruch&apos s basal membrane structure Cell physiology Cells Cellular Structures Cholesterol Choroid Complement Complex Confocal Microscopy Defect Deposition Deterioration Diagnostic Diagnostic Procedure Disease Disease Progression Doctor of Philosophy Doyne honeycomb retinal dystrophy Drug Delivery Systems Drug Targeting Electron Microscope Evaluation Exhibits Extracellular Matrix Eye Eye diseases Foundations Functional disorder Genetic Glucose Goals Health Histologic Hour Human Image Impairment Individual Inherited Lasers Light Light Microscope Link Lipids Macular degeneration Maps Measurement Measures Methods Modeling Molecular Morphology Mus Mutation Natural regeneration Nutrient Ophthalmoscopes Opsin Optical Coherence Tomography Optics Oxidation-Reduction Oxygen Pathology Patients Pharmaceutical Preparations Photoreceptors Point Mutation Population Prevalence Recycling Resolution Retina Retinal Cone Retinal Degeneration Retinal Photoreceptors Retinal Pigments Retinoids Rhodopsin Rod Role S1-5 protein Scanning Stress Structure Structure of retinal pigment epithelium Surface Tail Testing Therapeutic Therapeutic Agents Thick Time Tissues Validation Variant Veins Visual impairment Vitamin A adaptive optics adaptive optics scanning laser ophthalmoscopy age related base capillary bed cell type cohort confocal imaging extracellular imaging modality in vivo in vivo imaging innovation mitochondrial dysfunction mouse model multimodality nanoparticle nanoparticle delivery nanotherapy neurovascular unit novel novel diagnostics ocular imaging particle retinal rods targeted treatment theranostics tool

项目摘要

TITLE: Theranostics of Photoreceptor-RPE-Choroid Neurovascular Unit in Mouse Models of Eye Diseases PI: Robert J. Zawadzki, Ph.D. SUMMARY Inherited and age-related macular degeneration (AMD) are currently responsible for serious vision impairment in over 2 million US residents, with prevalence expected to double by 2040 as the population ages. Degeneration occurs in photoreceptor cells, retinal pigment epithelial (RPE) cells and in the choroidal vasculature, a complex of tightly interdependent tissues in the posterior eye. This project will investigate in vivo the photoreceptor-RPE-choroid complex in animal models of two macular degenerations, RPE mitochondrial dysfunction model and Doyne Honeycomb Retinal Dystrophy. These models recapitulate two major hallmarks of inherited and age related macular degeneration, degeneration of RPE cells, and age- related increase in extracellular deposits between the RPE and Bruch's membrane, which separates the RPE from the choroidal capillary bed. The project will use innovative, cellular-level resolution in vivo imaging combined with additional functional tests to characterize age-related changes in the structure and function of cells of the photoreceptor-RPE-choroid neurovascular unit (PRC-NVU). These studies will be performed longitudinally in cohorts of mice with the genetic defects, and in wild type controls. The studies will test the hypothesis that the primary defects in RPE-Bruch's membrane cause secondary deterioration of photoreceptors and choriocapillaris vasculature. The studies include measures of photoreceptor structure and electrical activity, bleaching and regeneration of the rod visual pigment rhodopsin, mapping of Bruch's membrane thickness, RPE cell autofluorescence, the redox status of RPE cells, and choriocapillaris vascular morphology and flow. At the termination of the study, the choroid-RPE from one eye of each mouse will be imaged with high resolution ex vivo confocal microscopy; the retina from the second eye of each mouse will be evaluated by conventional histological and biochemical measurements performed on light or electron microscopes, to allow validation of in vivo findings. A novel method for delivering drugs to the RPE via near infrared light-degradable nanoparticles will be used to locally target therapeutic agents to ailing RPE cells, and spatially resolved imaging will be used to determine if the therapeutic agents slow and stop disease progression. By combining longitudinal, in vivo imaging and optical nanotherapies, these studies will lay a foundation for locally targeted drug delivery in human ocular disease.

标题：鼠标疾病模型中光感受器-RPE-舌神经血管单元的疗法 PI：Robert J. Zawadzki，博士概括遗传和与年龄有关的黄斑变性（AMD）目前负责严重视力障碍在超过200万的美国居民中，随着人口年龄的增长，预计到2040年的流行率将翻一番。变性发生在感光细胞，视网膜色素上皮（RPE）和脉络膜中脉管系统，后眼中紧密相互依赖的组织的复合物。该项目将在在两个黄斑变性的动物模型中，体内光感受器-RPE-甲状腺复合体RPE 线粒体功能障碍模型和Doyne Honeycomb视网膜营养不良。这些模型概括了两个遗传和与年龄相关的黄斑变性，RPE细胞变性以及年龄的主要标志 RPE和BRUCH膜之间的细胞外沉积相关增加，这将RPE分开从脉络膜毛细管床。该项目将在体内成像中使用创新的蜂窝级分辨率结合其他功能测试，以表征与年龄相关的结构和功能的变化光感受器-RPE-螺布神经血管单元（PRC-NVU）的细胞。这些研究将进行与遗传缺陷和野生型对照组的小鼠队列中的纵向。研究将测试 RPE-Bruch膜中的主要缺陷导致次要恶化的假设感光体和绒毛膜乳房脉管系统。研究包括光感受器结构的度量以及杆视觉色素视紫红蛋白的电活动，漂白和再生，Bruch的映射膜厚度，RPE细胞自动荧光，RPE细胞的氧化还原状态和脉络膜毛细血管血管形态和流动。在研究终止时，每只小鼠一只眼睛的脉络膜rpe将是用高分辨率离体共聚焦显微镜成像；每只鼠标第二眼的视网膜将是通过在光或电子上进行的常规组织学和生化测量评估显微镜，允许验证体内发现。一种新的方法，可以通过附近将药物输送到RPE 红外降解的纳米颗粒将用于局部靶向治疗剂，以使RPE细胞和靶向纳米粒子，并将其靶向。空间分辨的成像将用于确定治疗剂是否缓慢并阻止疾病进展。通过结合纵向，体内成像和光学纳米疗法，这些研究将奠定人类眼部疾病中局部靶向药物的基础。