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：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 PI：Robert J. Zawadzki，博士概括遗传性和年龄相关性黄斑变性 (AMD) 目前是导致严重视力障碍的原因在超过 200 万美国居民中，随着人口老龄化，到 2040 年，患病率预计将翻一番。变性发生在感光细胞、视网膜色素上皮 (RPE) 细胞和脉络膜中脉管系统，后眼中紧密相互依赖的组织的复合体。该项目将调查两种黄斑变性动物模型中的光感受器-RPE-脉络膜复合体，RPE 线粒体功能障碍模型和 Doyne 蜂窝状视网膜营养不良。这些模型概括了两个遗传性和年龄相关性黄斑变性、RPE 细胞变性和年龄相关性的主要特征 RPE 和布鲁赫膜（将 RPE 分开）之间的细胞外沉积物相关增加来自脉络膜毛细血管床。该项目将使用创新的细胞级分辨率体内成像结合额外的功能测试来表征与年龄相关的结构和功能变化光感受器-RPE-脉络膜神经血管单元（PRC-NVU）的细胞。这些研究将进行在具有遗传缺陷的小鼠组和野生型对照小鼠中进行纵向研究。研究将测试假设 RPE-Bruch 膜的主要缺陷会导致 RPE-Bruch 膜的二次劣化光感受器和脉络膜毛细血管系统。这些研究包括光感受器结构的测量和电活动、视杆视色素视紫红质的漂白和再生，布鲁赫的绘图膜厚度、RPE 细胞自发荧光、RPE 细胞的氧化还原状态和脉络膜毛细血管形态和流动。研究结束时，每只小鼠一只眼睛的脉络膜 RPE 将被记录使用高分辨率离体共聚焦显微镜成像；每只小鼠第二只眼的视网膜将是通过对光或电子进行的常规组织学和生化测量进行评估显微镜，以验证体内发现。一种通过近端向 RPE 输送药物的新方法红外光可降解纳米颗粒将用于将治疗药物局部靶向患病的 RPE 细胞，以及空间分辨成像将用于确定治疗药物是否减缓和阻止疾病进展。通过结合纵向、体内成像和光学纳米疗法，这些研究将奠定为人类眼部疾病局部靶向药物输送奠定了基础。