Multimodal Molecular Imaging of Choroidal Neovascularization

项目摘要/摘要 湿性老年性黄斑变性(AMD)是导致青光眼不可逆失明的主要原因。 发达国家。脉络膜新生血管(CNV)是AMD导致视力丧失的主要原因。虽然 抗血管内皮生长因子(VEGF)治疗在CNV治疗方面显示出重大突破， 持续性疾病活动(PDA)很常见。在接受治疗的患者中，53%和71%的患者表现出PDA 每月分别服用雷尼比珠单抗和贝伐单抗。20%的患者在法律上失明，另有 30%的人在接受抗血管内皮生长因子治疗5年后出现不同程度的视力丧失。虽然AMD是一个严重的问题， 在临床前环境中测试新疗法的能力受到限制的一个关键障碍是缺乏CNV动物 PDA模型和缺乏纵向监测疾病生物标志物和反应的方法 心理治疗。该项目的目标是开发最先进的非侵入性多模式分子成像 并通过PDA对新的CNV兔模型成像生物标志物的纵向评价提供平台 用于开发新疗法的技术。 我们已经开发出一种高分辨率、多模式的眼科成像系统，包括 光声显微镜(PAM)、光学相干层析成像(OCT)和荧光显微镜(FM)。 开发了新型链状金纳米粒子簇，并将其用于增强分子成像和 靶向整合素存在于CNV中。我们还利用年长的兔子开发了一种健壮的PDA动物模型 对抗血管内皮生长因子治疗的反应最小。受到这些令人振奋的初步结果的鼓舞，我们 建议进一步开发AMD的这一平台分子成像技术，中心假设是 能够评估CNV动物模型的多模式分子成像系统可能有助于 了解AMD的基础生物学和治疗新药物疗法的发展 CNV.我们将通过以下具体目标来验证我们的假设：目标1：升级多模式PAM，OCT， 兔眼实时成像的调频系统。目的2：检验幼兔健壮的预测 抗血管内皮生长因子抗体的反应表现为毛细血管新生血管，而老年兔则表现为微动脉新生血管 通过多模式成像进行可视化。目的3：验证兔CNV模型对抗体应答的预测 利用超微型链状金驱动的多模式成像，可以在分子水平上可视化血管内皮生长因子 纳米粒子。这项工作的结果将包括未来研究的概念、工具和策略 几个学科：a)AMD基础生物学，以可视化和量化，具有高度的空间和时间 活体动物的分辨率、功能和分子变化。B)测试和开发小说的战略 大眼球模型的药物和非药物治疗，特别是对伴有PDA的CNV。C)改进 预测研究使治疗反应的实时分子生物标志物成为可能。

PROJECT SUMMARY/ABSTRACT Wet age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. Choroidal neovascularization (CNV) is the leading cause of vision loss due to AMD. Although anti-vascular endothelial growth factor (VEGF) therapy has shown a great breakthrough in CNV treatment, persistent disease activity (PDA) is common. PDA has been demonstrated in 53% and 71% of patients treated monthly with ranibizumab and bevacizumab, respectively. 20% of patients become legally blind and another 30% suffer from some degree of vision loss after 5 years of anti-VEGF therapy. While AMD is a serious problem, one critical barrier limiting the ability to test novel therapies in preclinical settings is the lack of CNV animal models with PDA and the lack of methods for longitudinal monitoring of disease biomarkers and response to therapy. The goal of this project is to develop state-of-the-art multimodal molecular imaging for non-invasive and longitudinal assessment of the imaging biomarkers in a new CNV rabbit model with PDA to offer a platform technology for the development of novel therapeutics. We have developed a high resolution, multimodal ophthalmic imaging system incorporating photoacoustic microscopy (PAM), optical coherence tomography (OCT), and fluorescence microscopy (FM). Novel chain-like gold nanoparticle clusters have been developed and used to enhance molecular imaging and target integrins present in CNV. We have also developed a robust animal model of PDA using older rabbits that demonstrate minimal response to anti-VEGF therapy. Encouraged by these exciting preliminary results, we propose to further develop this platform molecular imaging technology for AMD with a central hypothesis that a multimodal molecular imaging system that can evaluate the CNV animal model could contribute to understanding the fundamental biology of AMD and the development of new pharmaceutical therapies to treat CNV. We will test our hypothesis with the following Specific Aims: Aim 1: Upgrade the multimodal PAM, OCT, and FM system for real-time imaging in rabbit eyes. Aim 2: Test the prediction that young rabbits with robust response to anti-VEGF demonstrate capillary CNV while older rabbits demonstrate arteriolar CNV that can be visualized with multimodal imaging. Aim 3: Test the prediction that the rabbit models of CNV in response to anti- VEGF can be visualized at a molecular level with multimodal imaging powered by ultraminiature chain-like gold nanoparticles. The results of this work will include concepts, tools, and strategies for future research across several disciplines: a) Fundamental biology of AMD to visualize and quantify, with high spatial and temporal resolution, functional and molecular changes in living animals. b) Strategies for testing and developing novel drugs and non-pharmaceutical therapies in large eye models, particularly for CNV with PDA. c) Improved prognostication research to enable real-time molecular biomarkers of treatment response.