Multimodal Molecular Imaging of Choroidal Neovascularization

脉络膜新生血管的多模态分子成像

• 批准号: 10736104
• 负责人: Yannis Mantas Paulus
• 金额: $ 67.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736104
• 关键词: Age related macular degeneration; Aging; Animal Model; Animals; Biological Markers; Biology; Blindness; Blood Vessels; Blood capillaries; Characteristics; Choroidal Neovascularization; Clinical assessments; Contrast Media; Development; Discipline; Disease; Ensure; Excretory function; Exhibits; Eye; Eye diseases; Fluorescence Microscopy; Functional Imaging; Goals; Histology; Image; Image Enhancement; Imaging technology; Immunohistochemistry; Integrin alphaVbeta3; Integrins; Legal Blindness; Light; Macular degeneration; Methods; Microscopy; Modeling; Molecular; Molecular Target; Monitor; Morphologic artifacts; Motion; Multimodal Imaging; Optical Coherence Tomography; Oryctolagus cuniculus; Pathologic; Patients; Peptides; Performance; Pharmacologic Substance; Population; Real-Time Systems; Renal clearance function; Research; Resolution; Safety; Scanning; Speed; System; Testing; Time; Toxic effect; United States; Urine; Vascular Endothelial Growth Factors; Visualization; Work; bevacizumab; biomaterial compatibility; clinically relevant; imaging biomarker; imaging modality; imaging platform; imaging system; improved; in vivo; invention; legally blind; matrigel; microscopic imaging; molecular imaging; molecular marker; multimodality; nanoGold; nanoparticle; non-invasive imaging; novel; novel therapeutics; pre-clinical; predicting response; prognostication; ranibizumab; real-time images; research and development; response; serial imaging; sound; subretinal injection; technology development; technology platform; temporal measurement; tool; translational impact; treatment response; Age related macular degeneration; Aging; Animal Model; Animals; Biological Markers; Biology; Blindness; Blood Vessels; Blood capillaries; Characteristics; Choroidal Neovascularization; Clinical assessments; Contrast Media; Development; Discipline; Disease; Ensure; Excretory function; Exhibits; Eye; Eye diseases; Fluorescence Microscopy; Functional Imaging; Goals; Histology; Image; Image Enhancement; Imaging technology; Immunohistochemistry; Integrin alphaVbeta3; Integrins; Legal Blindness; Light; Macular degeneration; Methods; Microscopy; Modeling; Molecular; Molecular Target; Monitor; Morphologic artifacts; Motion; Multimodal Imaging; Optical Coherence Tomography; Oryctolagus cuniculus; Pathologic; Patients; Peptides; Performance; Pharmacologic Substance; Population; Real-Time Systems; Renal clearance function; Research; Resolution; Safety; Scanning; Speed; System; Testing; Time; Toxic effect; United States; Urine; Vascular Endothelial Growth Factors; Visualization; Work; bevacizumab; biomaterial compatibility; clinically relevant; imaging biomarker; imaging modality; imaging platform; imaging system; improved; in vivo; invention; legally blind; matrigel; microscopic imaging; molecular imaging; molecular marker; multimodality; nanoGold; nanoparticle; non-invasive imaging; novel; novel therapeutics; pre-clinical; predicting response; prognostication; ranibizumab; real-time images; research and development; response; serial imaging; sound; subretinal injection; technology development; technology platform; temporal measurement; tool; translational impact; treatment response

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.

项目摘要/摘要 与年龄相关的黄斑变性（AMD）是导致不可逆失明的主要原因 发达世界。脉络膜新血管形成（CNV）是AMD引起的视力丧失的主要原因。虽然 抗血管内皮生长因子（VEGF）疗法在CNV治疗中表现出了很大的突破， 持续性疾病活动（PDA）很常见。 PDA已在53％和71％的患者中被证明 分别与ranibizumab和bevacizumab一起每月一次。 20％的患者在法律上成为盲人，另一个患者 5年的抗VEGF治疗后，有30％的人患有一定程度的视力丧失。虽然AMD是一个严重的问题，但 限制临床前环境中测试新疗法的能力的一个关键障碍是缺乏CNV动物 PDA的模型以及缺乏纵向监测疾病生物标志物的方法以及对 治疗。该项目的目的是开发最新的多模式分子成像，以进行非侵入性 以及使用PDA的新的CNV兔模型中对成像生物标志物的纵向评估，以提供平台 开发新型治疗学的技术。 我们已经开发了高分辨率的多模式眼科成像系统 光声显微镜（PAM），光学相干断层扫描（OCT）和荧光显微镜（FM）。 新型链状金纳米颗粒簇已经开发并用于增强分子成像和 CNV中存在的靶总素。我们还使用旧兔子开发了一种强大的PDA动物模型 证明对抗VEGF疗法的反应最少。在这些令人兴奋的初步结果的鼓励下，我们 提议进一步开发AMD的平台分子成像技术，并以中心假设为假设 可以评估CNV动物模型的多模式分子成像系统可能有助于 了解AMD的基本生物学以及新的药物治疗的开发 CNV。我们将以以下特定目的测试我们的假设：目标1：升级多模式PAM，OCT， 和FM系统，用于兔子眼中的实时成像。 AIM 2：测试年轻兔子强大的预测 对抗VEGF的反应证明了毛细血管CNV，而较老的兔子表现出可以是动脉CNV 用多模式成像可视化。 AIM 3：测试CNV兔模型响应抗 - 的预测 VEGF可以在分子水平上以多模式成像为单位，由超显链链样黄金供电 纳米颗粒。这项工作的结果将包括概念，工具和策略，以使未来的研究跨越 几个学科：a）AMD的基本生物学可视化和量化，具有高空间和时间的生物学 生物动物的分辨率，功能和分子变化。 b）测试和发展新颖的策略 大眼模型中的药物和非药物疗法，尤其是用于PDA的CNV。 c）改进 预测研究以实现治疗反应的实时分子生物标志物。