In vivo Ultrastructure of Chorioretinal Disease

项目摘要 这次更新将解决视网膜下玻璃纤维瘤样沉积物（SDD）导致的途径中的关键知识空白。 年龄相关性黄斑病变中的3型黄斑新生血管（T3 MNV，也称为视网膜血管瘤样增生） 退行性变（AMD）。SDD是存在于光感受器和其支持视网膜之间的细胞外病变 色素上皮（RPE）细胞。因此，它们位于生理性血视网膜屏障的对侧， 玻璃疣，这是AMD的标志性病变。玻璃疣积聚在Bruch膜后的内表面 到RPE。T3 MNV是一种重要的但较少被认识的新生血管性AMD形式，其具有视网膜内起源， 会导致严重的视力丧失SDD在T3 MNV眼中的发生率非常高。的分布 T3 MNV与SDD有很大的重叠。T3 MNV的病因最近被先进的视网膜成像所认识 包括光学相干断层扫描（OCT）结构和血管造影（OCTA）。有人认为T3 MNV 在视网膜色素上皮细胞向前迁移后，起源于视网膜的深毛细血管丛（DCP）。SDD如何 导致T3 MNV，以及视网膜毛细血管如何与前体迁移性RPE细胞相互作用以启动T3 MNV， 完全理解也不是RPE细胞开始迁移的原因和时间。我们假设减少或受损的 由于脉络膜毛细血管功能障碍或两侧细胞外病变的积累而导致的代谢供应 RPE是促进RPE细胞离开其单层并迁移到DCP的刺激事件，从而 引起视网膜中的新血管形成; SDD可显著加剧该过程。因此，我们建议， 通过视网膜毛细血管的体内表征来评估视网膜毛细血管系统的健康状态 血液动力学与SDD和玻璃疣的发展阶段、RPE的健康和结构的关系 的脉络膜毛细血管和脉络膜，在AMD患者。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），其可以以细胞分辨率对视网膜成像， 测量视网膜毛细血管中的高阶血流动力学。我们开发了一种新的方法来估计 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。我们的目标是双重的：了解SDD导致T3 MNV的途径， 开发基于AO成像的生物标志物用于T3 MNV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的加速度（及其变化）的特性可以提供 灵敏地检测由早期新生血管事件引起的视网膜微循环异常， T3MNV 2. FLIO可以提供与SDD的阶段相关的RPE健康的客观量化， 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T3 MNV，从而， 代表着我们朝着长期目标迈出的重要一步，该目标致力于改善评估风险的基础， 用于评估治疗的AMD进展和临床终点。

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.