In vivo Ultrastructure of Chorioretinal Disease

脉络膜视网膜疾病的体内超微结构

• 批准号: 10212112
• 负责人: Yuhua Liang Zhang
• 金额: $ 33.95万
• 依托单位: DOHENY EYE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212112
• 关键词: Acceleration; Address; Age; Age related macular degeneration; Angiography; Anterior; Atrophic; Basal lamina; Blindness; Blood Vessels; Blood capillaries; Blood flow; Blood-Retinal Barrier; Bruch' s basal membrane structure; Characteristics; Choroid; Clinical; Deposition; Detection; Development; Disease; Drusen; Etiology; Event; Evolution; Exudative age-related macular degeneration; Eye; Fluorescence; Functional disorder; Funding; Gender; Goals; Health; Health Status; Image; Imaging Techniques; Impairment; Individual; Knowledge; Lead; Lesion; Letters; Measurement; Measures; Metabolic; Methods; Microcirculation; Monitor; Multimodal Imaging; Natural History; Ophthalmoscopes; Ophthalmoscopy; Optical Coherence Tomography; Paper; Pathway interactions; Patients; Peer Review; Perfusion; Photoreceptors; Physiological; Procedures; Process; Race; Research; Resolution; Retina; Risk; Side; Specific qualifier value; Speed; Structure; Structure of retinal pigment epithelium; Surface; System; Testing; adaptive optics; cell motility; cohort; density; early detection biomarkers; extracellular; fluorescence lifetime imaging; hemodynamics; high resolution imaging; imaging biomarker; improved; in vivo; macula; migration; monolayer; neovascular; neovascularization; neurosensory; novel; retinal imaging; success

Project Summary This renewal will address crucial knowledge gaps in the pathway that subretinal drusenoid deposits (SDD) lead to Type 3 macular neovascularization (T3MNV, also known as retinal angiomatous proliferation) in age-related macular degeneration (AMD). SDD are extracellular lesions present between photoreceptors and their supportive retinal pigment epithelium (RPE) cells. Thus they’re on the opposite side of the physiologic blood-retina-barrier to classical drusen, which are AMD’s hallmark lesions. Drusen accumulate on the inner surface of Bruch’s membrane posterior to the RPE. T3MNV is an important by less recognized form of neovascular AMD that has an intraretinal origin and can result in severe vision loss. SDD have a strikingly high occurrence in eyes with T3MNV. The distribution of T3MNV has a large overlap with that of SDD. T3MNV’s etiology is recently appreciated by advanced retinal imaging including optical coherence tomography (OCT) structure and angiography (OCTA). It’s been suggested that T3MNV originates from the deep capillary plexus (DCP) of the retina after precursory RPE cells migrate anteriorly. How SDD lead to T3MNV, and how retinal capillaries interact with precursor migratory RPE cells to initiate T3MNV is not completely understood. Nor is why and when RPE cells begin migration. We hypothesize that reduced or impaired metabolic supply due to dysfunction of the choriocapillaris or accumulation of extracellular lesions on both sides of the RPE are inciting events that promote RPE cells to leave their monolayer and migrate to the DCP, thereby eliciting neovascularization in the retina; this process can be significantly exacerbated by SDD. We thus propose to evaluate the health status of the retinal capillary system through in vivo characterization of the retinal capillary hemodynamics in relation to the developmental stage of SDD and drusen, the health of the RPE, and the structure of the choriocapillaris and the choroid, in patients with AMD. We’ve developed an adaptive optics (AO) enhanced high speed near confocal ophthalmoscope (AONCO), which can image the retina with cellular resolution and measure the high-order hemodynamics in retinal capillaries. We've developed novel method to estimate the choriocapillaris structure using OCTA. We obtained fluorescence lifetime imaging ophthalmoscopy (FLIO), which can assess RPE health. Our objectives are two-fold: understanding the pathway by which SDD lead to T3MNV and developing AO imaging based biomarkers for early detection of T3MNV. We predict: 1. High-order hemodynamic characteristics that measure the acceleration (and its change) of the blood flow within retinal capillaries may provide sensitive detection of abnormalities of the retinal microcirculation induced by early neovascular events that lead to T3MNV. 2. FLIO may provide an objective quantification of RPE health that correlates with the stages of SDD and drusen, and the health of the choriocapillaris. Success of this research will provide improved markers and endpoint for monitoring and treating T3MNV by objective measurements of RPE health and retinal vascular health, thereby, represents a significant stride toward our long-term goal that dedicates to improve the basis of assessing risk for AMD progression and clinical endpoints for evaluating treatments.

项目概要 这一更新将解决视网膜下玻璃疣样沉积物（SDD）导致的途径中的关键知识差距 年龄相关性黄斑中的 3 型黄斑新生血管（T3MNV，也称为视网膜血管瘤增殖） 变性（AMD）。 SDD 是光感受器及其支持性视网膜之间存在的细胞外病变 色素上皮（RPE）细胞。因此，它们位于经典血视网膜生理屏障的另一侧 玻璃疣，这是 AMD 的标志性病变。玻璃疣积聚在布鲁赫后膜内表面 到 RPE。 T3MNV 是一种重要但鲜为人知的新生血管性 AMD 形式，其起源于视网膜内，并且 可能导致严重的视力丧失。 SDD have a strikingly high occurrence in eyes with T3MNV.的分布 T3MNV 与 SDD 有很大的重叠。 T3MNV 的病因最近被先进的视网膜成像技术所认识 包括光学相干断层扫描（OCT）结构和血管造影（OCTA）。有人建议 T3MNV 前体RPE细胞向前迁移后，起源于视网膜深部毛细血管丛（DCP）。如何SDD 导致 T3MNV，而视网膜毛细血管如何与前体迁移 RPE 细胞相互作用以引发 T3MNV 尚不清楚 完全明白了。也不是 RPE 细胞开始迁移的原因和时间。我们假设减少或损害 由于脉络膜毛细血管功能障碍或两侧细胞外病变堆积导致代谢供应 RPE 正在引发事件，促进 RPE 细胞离开单层并迁移到 DCP，从而 引起视网膜新生血管形成； SDD 可能会显着加剧这一过程。因此我们建议 通过视网膜毛细血管的体内表征评估视网膜毛细血管系统的健康状况 与 SDD 和玻璃膜疣的发育阶段、RPE 的健康状况及其结构相关的血流动力学 AMD 患者的脉络膜毛细血管和脉络膜。我们开发了一种自适应光学 (AO) 增强型 高速近共焦检眼镜 (AONCO)，可以以细胞分辨率对视网膜进行成像， 测量视网膜毛细血管的高阶血流动力学。我们开发了一种新颖的方法来估计 使用 OCTA 绘制脉络膜毛细血管结构。我们获得了荧光寿命成像检眼镜 (FLIO)， 可以评估 RPE 健康状况。我们的目标有两个：了解 SDD 导致 T3MNV 的途径以及 开发基于 AO 成像的生物标志物，用于 T3MNV 的早期检测。我们预测： 1. 高阶血流动力学 测量视网膜毛细血管内血流加速度（及其变化）的特征可以提供 敏感地检测早期新生血管事件引起的视网膜微循环异常，从而导致 T3MNV。 2. FLIO 可以提供与 SDD 阶段相关的 RPE 健康状况的客观量化 玻璃疣和脉络膜毛细血管的健康。这项研究的成功将提供改进的标志物和终点 通过客观测量 RPE 健康和视网膜血管健康来监测和治疗 T3MNV，从而， 代表着我们朝着致力于改善风险评估基础的长期目标迈出了一大步 AMD 进展和评估治疗的临床终点。