Imaging of Retinal Hydroxyapatite as an Early Screen for AMD

视网膜羟基磷灰石成像作为 AMD 的早期筛查

基本信息

批准号：
10630229
负责人：
RICHARD Blair THOMPSON
金额：
$ 43.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10630229
关键词：
Affect Age related macular degeneration American Animal Disease Models Animal Model Animals Antibiotics Appearance Behavior Binding Biological Markers Biomedical Engineering Blindness Bone Growth Cadaver Cause of Death Cells Clinical Cues Data Deposition Developed Countries Development Disease Drug Kinetics Drusen Dryness Early Diagnosis Elderly Fatty acid glycerol esters Fluorescence Fundus Growth High Fat Diet Human Hydroxyapatites Image Imaging Techniques In Vitro Japanese Monkey Light Macaca Macaca mulatta Microscopic Minerals Modeling Monkeys Morphology Onset of illness Ophthalmoscopes Oral Administration Patients Persons Pharmaceutical Preparations Phototoxicity Pigment Epithelium Probability Procedures Process Proteins Research Project Grants Retina Safety Site Specimen Stains Techniques Testing Tetracyclines Tooth structure Toxic effect Vegf Inhibitor aged bone calcium phosphate contrast imaging design early screening fluorescence imaging fluorescence lifetime imaging fovea centralis human subject imaging approach imaging modality improved in vivo in vivo imaging instrument macula novel ophthalmic examination pill reduce symptoms response retinal imaging screening usability

项目摘要

Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly in developed countries, affecting over ten million Americans. The disease onset is gradual, with few symptoms and most patients unaware until irreversible vision loss is detected by eye examination. It is accepted that the buildup of deposits of fats and protein in the retina, the best known of which are called drusen, causes the death of the light-sensitive cells there. While the less common, “wet” form of AMD (CNV) can be arrested by drugs called VEGF inhibitors, the more common, “dry” form (GA) is currently untreatable, although several treatments are in development. Recently, we discovered that drusen contain microscopic spherules of hydroxyapatite (HAP), a form of calcium phosphate abundant in bones and teeth, and developed evidence indicating that the spherules nucleate the growth of drusen in the retina. We found that fluorescent stains developed to study bone growth would also stain the spherules, permitting them to be studied by fluorescence imaging of the retina. We inferred that detecting the HAP spherules early by such an imaging approach used in vivo might predict the appearance of the drusen and thus AMD development; this was confirmed in at least some cases. Thus, the thrust of this Bioengineering Research Grant is to develop and validate a retinal imaging approach for screening and early detection of AMD, both to cue treatment, and to follow the course of the disease to assess treatment. Some of the stains synthesized for bone studies in animal models perform well in vitro, but their behavior and safety is little known in animals, and there are no human studies at all. However, some tetracycline antibiotics also give bright fluorescence when bound to bone mineral, and we found that they have a distinct fluorescence lifetime under these conditions, which can be resolved from the background fluorescence of the retina by fluorescence lifetime imaging. The tetracyclines have well known behavior, can probably be administered orally, and are very safe in humans. To image the spherules with tetracycline staining we must construct a fluorescence lifetime imaging ophthalmoscope (FLIO), usable on humans or the only good animal model for AMD, macaques (monkeys). We will construct a FLIO based on an existing instrument, refine our procedures on donor cadavers, then test the FLIO and staining procedures on aged macaques (which develop spherules) and a Japanese macaque which develops drusen early and rapidly as a result of a high fat diet. Key questions to be answered are how reliably the appearance of spherules predicts the development of drusen and progression to AMD, and how safe the imaging procedure is for the monkeys; satisfactory results will likely lead to trials in humans.

年龄相关性黄斑变性（AMD）是发达国家老年人失明的最常见原因影响超过 1000 万美国人的疾病是渐进的，症状很少，而且症状最多。直到通过眼科检查发现不可逆的视力丧失时，患者才会意识到。视网膜上的脂肪和蛋白质沉积物，其中最著名的是玻璃疣，会导致视网膜死亡。那里的光敏感细胞虽然不太常见，但“湿”形式的 AMD (CNV) 可以被称为“湿”的药物抑制。 VEGF 抑制剂是更常见的“干”形式 (GA)，目前无法治疗，尽管有几种治疗方法正在研究中最近，我们发现玻璃膜疣含有羟基磷灰石（HAP）的微观球粒，羟基磷灰石是一种磷酸钙的形式在骨骼和牙齿中含量丰富，并有证据表明小球我们发现荧光染色剂可用于研究骨骼生长。还会对球体进行染色，从而可以通过视网膜荧光成像来研究它们。推断通过体内使用的这种成像方法早期检测 HAP 小球可能会预测玻璃膜疣的出现以及 AMD 的发展；这至少在某些情况下得到了证实。因此，这项生物工程研究补助金的主旨是开发和验证视网膜成像方法用于 AMD 的筛查和早期检测，既可以提示治疗，也可以跟踪病程以一些为动物模型骨骼研究而合成的染色剂在体外表现良好，但是人们对它们的行为和安全性知之甚少，也根本没有进行过人类研究。四环素抗生素与骨矿物质结合时也会发出明亮的荧光，我们发现它们具有在这些条件下具有不同的荧光寿命，可以从背景中解析通过荧光寿命成像观察视网膜的荧光四环素具有众所周知的行为，可以可能是口服给药，并且对人类来说非常安全。用四环素对小球进行成像。我们必须构建一个荧光寿命成像检眼镜（FLIO），可用于人类或 AMD 唯一好的动物模型是猕猴（猴子），我们将在现有的基础上构建 FLIO。仪器，完善我们在捐献者尸体上的程序，然后在老年人身上测试 FLIO 和染色程序猕猴（发育出小球）和日本猕猴，其早期且迅速地形成玻璃膜疣需要回答的关键问题是小球的出现预测的可靠性如何。玻璃膜疣的发展和 AMD 的进展，以及成像过程对猴子的安全性；令人满意的结果可能会导致人体试验。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bruch's Membrane Calcification in Pseudoxanthoma Elasticum: Comparing Histopathology and Clinical Imaging.

弹性假黄瘤中的布鲁赫膜钙化：比较组织病理学和临床影像。

DOI：
发表时间：
2024
期刊：
影响因子：
0
作者：
Risseeuw, Sara;Pilgrim, Matthew G;Bertazzo, Sergio;Brown, Connor N;Csincsik, Lajos;Fearn, Sarah;Thompson, Richard B;Bergen, Arthur A;Ten Brink, Jacoline B;Kortvely, Elod;Spiering, Wilko;Ossewaarde;van Leeuwen, Redmer;Leng
通讯作者：
Leng

Fluorescent Arylphosphonic Acids: Synergic Interactions between Bone and the Fluorescent Core.

荧光芳基膦酸：骨和荧光核心之间的协同相互作用。

DOI：
发表时间：
2020-09-01
期刊：
影响因子：
0
作者：
Zorlu, Yunus;Brown, Connor;Keil, Claudia;Ayhan, M Menaf;Haase, Hajo;Thompson, Richard B;Lengyel, Imre;Yücesan, Gündoğ
通讯作者：
Yücesan, Gündoğ

A 2,7-dichlorofluorescein derivative to monitor microcalcifications.

一种 2,7-二氯荧光素衍生物，用于监测微钙化。

DOI：
发表时间：
2022-11-01
期刊：
影响因子：
3.6
作者：
Tholen, Patrik;Brown, Connor N;Keil, Claudia;Bayir, Ali;Zeng, Hui;Haase, Hajo;Thompson, Richard B;Lengyel, Imre;Yücesan, Gündoğ
通讯作者：
Yücesan, Gündoğ

Fluorescence Lifetime Imaging of Human Sub-RPE Calcification In Vitro Following Chlortetracycline Infusion.

金霉素输注后人 RPE 体外钙化的荧光寿命成像。

DOI：
发表时间：
2023-03-29
期刊：
影响因子：
5.6
作者：
Hegde, Kavita R;Puche, Adam C;Szmacinski, Henryk;Fuller, Kristina;Ray, Krishanu;Patel, Nikita;Lengyel, Imre;Thompson, Richard B
通讯作者：
Thompson, Richard B

Two-Photon Excited Fluorescence Lifetime Imaging of Tetracycline-Labeled Retinal Calcification.

四环素标记的视网膜钙化的双光子激发荧光寿命成像。

DOI：
发表时间：
2023-07-24
期刊：
影响因子：
0
作者：
Hegde, Kavita R;Ray, Krishanu;Szmacinski, Henryk;Sorto, Sharon;Puche, Adam C;Lengyel, Imre;Thompson, Richard B
通讯作者：
Thompson, Richard B