In Vivo Molecular Imaging of Vascular Disease of the Retina

视网膜血管疾病的体内分子成像

• 批准号: 10116398
• 负责人: MD IMAM UDDIN
• 金额: $ 40.43万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116398
• 关键词: Address; Adult; Age; Age related macular degeneration; Air; Animal Model; Animals; Area; Biodistribution; Biological Assay; Biological Markers; Biology; Blood Vessels; Breathing; CASP3 gene; Clinical; Complication; Computer software; Computing Methodologies; Control Animal; Detection; Development; Diabetic Retinopathy; Diagnostic; Diagnostic Imaging; Drug Kinetics; Early Diagnosis; Evolution; Excision; Fluorescence; Goals; Health; High Pressure Liquid Chromatography; Hypoxia; Image; Imaging technology; Immunohistochemistry; In Situ Nick-End Labeling; In Vitro; KDR gene; Measurement; Measures; Mediating; Metabolism; Methods; Molecular; Monitor; Mus; Nuclear Magnetic Resonance; Optical Coherence Tomography; Oxygen; Oxygen saturation measurement; Pathogenesis; Pimonidazole; Plasma; Play; Proteins; Resolution; Retina; Retinal Diseases; Retinal Neovascularization; Retinal Vein Occlusion; Retinopathy of Prematurity; Risk; Role; Safety; Sample Size; Specimen; Statistical Data Interpretation; Techniques; Technology; Testing; Therapeutic Intervention; Time; Tissues; Toxic effect; Vascular Diseases; Visible Radiation; adduct; base; ex vivo imaging; experimental study; image processing; imaging modality; imaging probe; in vivo; in vivo imaging; liquid chromatography mass spectrometry; molecular imaging; mouse model; neovascularization; novel; ocular angiogenesis; phosphorescence; pre-clinical; preclinical study; predictive tools; pressure; response; retinal imaging; temporal measurement; tool

PROJECT SUMMARY Neovascularization (NV) is a common complication in age-related macular degeneration (AMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP) and retinal vein occlusion (RVO). Retinal hypoxia plays an important role during NV development and progression. Thus, in vivo molecular imaging of retinal hypoxia at an early stage could be an important predictive tool assessing the risk of NV development and progression. To this end, the PI has developed HYPOX-4, a highly sensitive molecular imaging probe capable of detecting retinal hypoxia in vivo in animal models of ROP and RVO. In this proposed study, quantitative assessment of HYPOX-4 fluorescence intensities measured by computational methods, correlating with levels of retinal hypoxia will be assessed to create a predictive tool for retinal NV development and progression. Current methods for the measurement of tissue oxygen tension include nuclear magnetic resonance, retinal oximetry, phosphorescence lifetime imaging, doppler optical coherence tomography (D-OCT), and visible-light OCT. Although their application has provided a clearer understanding of the vascular oxygen supply and metabolism in the retina, none of these imaging methods have been used successfully to measure retinal hypoxia in vivo within avascular retina or in ischemic tissues. Pimonidazole-adduct immunohistochemistry is the common method to study tissue hypoxia, but this technique is limited by it's exclusive ex vivo method of examination. Thus, it is not useful for ophthalmic clinical in vivo applications. To this end, HYPOX-4 (developed by the applicant) will be used to address the limitations of indirect or invasive hypoxia detection technologies. In Aim 1 and 2, HYPOX-4 will be tested to determine graded levels and temporal profiles of retinal hypoxia depicting the onset, evolution and resolution of NV in mouse model of oxygen-induced retinopathy (OIR) in vivo as well as ex vivo. Hypoxia profiles will be further correlated with the expression of hypoxia-associated biomarkers including HIF-1α, CAIX and VEGFR2. The standard pimonidazole-adduct ex vivo immunostaining and phosphorescence lifetime imaging will be performed in parallel experiments to confirm the temporal and graded retinal-hypoxia profiles and tissue oxygen pressures. In Aim 3, HYPOX-4 will be evaluated for biodistribution, safety and toxicity in this mouse OIR and room air (RA) control animals. In this proposal, the applicant (Dr. Uddin), experts in molecular imaging methods in the context of retinal vascular diseases and other types of vascular dysfunction, will collaborate with Dr. John Penn, Dr. Manaz Shahidi and Dr. Marnett, experts in biology of animal models and ocular angiogenesis to demonstrate the utility of this new hypoxia sensitive probe for the early detection of retinal hypoxia. These studies have significant potentials for advancing the implementation of molecular imaging technologies in preclinical and clinical settings, and to establish a novel method to investigate hypoxia as a component of retinal vasculopathies.

项目摘要 新血管形成（NV）是与年龄相关的黄斑变性（AMD），糖尿病的常见并发症 视网膜病变（DR），早产视网膜病变（ROP）和视网膜静脉闭塞（RVO）。视网膜缺氧发挥 在NV开发和发展过程中的重要作用。那是视网膜缺氧的体内分子成像 早期阶段可能是重要的预测工具评估NV开发和发展的风险。到 这一端，PI开发了Hypox-4，这是一种能够检测的高度敏感的分子成像探针 ROP和RVO动物模型中的视网膜缺氧。在这项拟议的研究中，定量评估 通过计算方法测量的Hypox-4荧光强度与视网膜水平相关 将评估缺氧以创建视网膜NV开发和进展的预测工具。当前的 测量组织氧张力的方法包括核磁共振，残留氧测量， 磷光寿命成像，多普勒光学相干断层扫描（D-OCT）和可见光OCT。 尽管他们的应用对血管氧供应和代谢有了更清晰的了解 在视网膜中，这些成像方法均未成功地测量体内视网膜缺氧 在血管视网膜或缺血组织中。 Pimonidazole-Adduct免疫组织化学是常见的 研究组织缺氧的方法，但该技术受到独家的离体检查方法的限制。 这对于眼科临床应用中的临床应用没有用。为此，hypox-4（由 申请人将用于解决间接或侵入性缺氧检测技术的局限性。目标 1和2，将测试Hypox-4，以确定残留缺氧描述的分级水平和临时谱。 NV在氧诱导的视网膜病变（OIR）体内的NV的开始，演变和分辨率 作为外体。低氧剖面将与缺氧相关的生物标志物的表达进一步相关 包括HIF-1α，CAIX和VEGFR2。标准的Pimonidazole-Adduct ex Vivo免疫染色和 磷光寿命成像将在平行实验中进行，以确认临时和 分级的视网膜 - 催产谱和组织氧压力。在AIM 3中，将评估Hypox-4 这款小鼠OIR和房间空气（RA）控制动物的生物分布，安全性和毒性。在此提案中， 申请人（Uddin博士），永久性血管疾病的分子成像方法专家 其他类型的血管功能障碍将与John Penn博士，Manaz Shahidi博士和Marnett博士合作， 动物模型和眼血管生成的生物学专家证明了这种新缺氧的效用 对视网膜缺氧早期检测的敏感探针。这些研究具有巨大的潜力 推进临床前和临床环境中分子成像技术的实施，并 建立一种新的方法来研究缺氧是视网膜血管病的组成部分。