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

• 批准号: 9236598
• 负责人: Robert J Zawadzki
• 金额: $ 34.82万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236598
• 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' 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; Drug Delivery Systems; Drug Targeting; Electron Microscope; Epithelial; Evaluation; Exhibits; Extracellular Matrix; Eye; Eye diseases; Foundations; Functional disorder; Genetic; Glucose; Goals; Health; Histologic; Hour; Human; Image; Impairment; Individual; Inherited; Injectable; 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; Retinal Cone; Retinal Degeneration; Retinal Dystrophy; Retinal Photoreceptors; Retinal Pigments; Retinoids; Rhodopsin; 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 age; cell type; cohort; extracellular; imaging modality; in vivo; in vivo imaging; innovation; mitochondrial dysfunction; mouse model; multimodality; nanoparticle; nanotherapy; neurovascular unit; novel; novel diagnostics; particle; retinal rods; targeted treatment; theranostics; tool

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.

光感受器-RPE-脉络膜神经血管单位在小鼠眼病模型中的病理学研究 PI：Robert J.Zawadzki，博士 摘要 遗传性和老年性黄斑变性(AMD)目前是严重视力障碍的原因 在200多万美国居民中，随着人口老龄化，患病率预计到2040年将翻一番。 变性发生在光感受器细胞、视网膜色素上皮(RPE)细胞和脉络膜 血管系统，眼球后部紧密相互依赖的组织的复合体。该项目将在 两种黄斑变性动物模型中感光细胞-RPE-脉络膜复合体的活体研究 线粒体功能障碍模型与多因蜂窝状视网膜营养不良。这些模型概括了两个 遗传性和老年性黄斑变性、RPE细胞变性和年龄的主要特征- RPE与分离RPE的Bruch膜之间的细胞外沉积相应增加 脉络膜毛细血管床。该项目将使用创新的细胞级活体成像 结合额外的功能测试来表征与年龄相关的结构和功能的变化 光感受器-RPE-脉络膜神经血管单位(PRC-NVU)的细胞。这些研究将被执行 纵向上，在具有遗传缺陷的小鼠队列中，在野生型对照中。这些研究将测试 假说RPE-Bruchs膜的原发缺陷导致继发性 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。 视紫红质视杆细胞的电活动、漂白和再生，Bruch‘s标测 膜厚度、RPE细胞的自发荧光、RPE细胞的氧化还原状态和脉络膜毛细血管 形态和流动。在研究结束时，每只小鼠一只眼睛的脉络膜RPE将被 用高分辨率体外共聚焦显微镜成像；每只小鼠第二只眼睛的视网膜将被 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，以验证体内的研究结果。一种通过NEAR将药物输送到RPE的新方法 红外线可光降解纳米颗粒将被用于局部靶向RPE细胞的治疗药物，以及 空间分辨成像将被用来确定治疗剂是否延缓和阻止疾病 进步。通过结合纵向、活体成像和光学纳米疗法，这些研究将奠定 人类眼病局部靶向给药基金会。