In vivo Ultrastructure of Chorioretinal Disease

项目摘要 这一更新将解决视网膜下玻璃体沉积(SDD)导致的关键知识缺口 老年性黄斑病变中的3型黄斑新生血管(T3MNV，又称视网膜血管瘤样增殖) 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损害 色素上皮(RPE)细胞。因此，它们处于生理血视网膜屏障的对立面 斑疹，这是AMD的标志性病变。玻璃体积聚在Bruch膜后内侧表面 送到RPE。T3MNV是一种重要的、但认识较少的新生血管性AMD，起源于视网膜内和 会导致严重的视力丧失。在T3MNV眼中SDD的发生率非常高。分布情况： T3MNV与SDD有较大重叠。T3MNV的病原学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)结构和血管成像(OCTA)。有人认为T3MNV 在前体RPE细胞向前方迁移后，起源于视网膜深部毛细血管丛(DCP)。如何使用SDD 导致T3MNV，视网膜毛细血管如何与前体迁移RPE细胞相互作用启动T3MNV 完全理解。也不知道RPE细胞为什么以及何时开始迁移。我们假设减少或削弱 由于脉络膜毛细血管功能障碍或两侧细胞外病变堆积所致的代谢供应 RPE正在激发促进RPE细胞离开其单层并迁移到DCP的事件，从而 诱导视网膜新生血管；SDD可显著加剧这一过程。因此，我们建议 通过视网膜毛细血管的活体表征评估视网膜毛细血管系统的健康状况 血流动力学与SDD和玻璃体病变的发育阶段、RPE的健康状况和结构的关系 脉络膜毛细血管和脉络膜，在AMD患者中。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)，它可以用细胞分辨率成像视网膜和 测量视网膜毛细血管的高阶血流动力学。我们开发了一种新的方法来估计 脉络膜毛细血管结构采用OCTA。我们获得了荧光寿命成像眼底镜(Flio)，它 可以评估RPE运行状况。我们的目标有两个：了解SDD导致T3MNV和 开发基于声学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的加速(及其变化)的特征可以提供 敏感检测早期新生血管事件导致的视网膜微循环异常 T3MNV。2.Flio可提供与SDD和SDD分期相关的RPE健康的客观量化 绒毛膜毛细血管的健康。这项研究的成功将提供更好的标志和终点 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进了一大步 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.