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：
10176510
负责人：
RICHARD Blair THOMPSON
金额：
$ 43.65万
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/10176510
关键词：
Affect Age related macular degeneration American Animal Disease Models Animal Model Animals Antibiotics Appearance Behavior Biological Markers Biomedical Engineering Blindness Bone Growth Cadaver Cause of Death Cells Clinical Cues Data Deltastab Deposition Developed Countries Development Disease Drug Kinetics Drusen 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 Ophthalmic examination and evaluation Ophthalmoscopes Oral Oral Administration Patients Pharmaceutical Preparations Phototoxicity Pigment Epithelium Procedures Process Proteins Research Project Grants Retina Safety Site Specimen Stains Symptoms Techniques Testing Tetracyclines Tooth structure Toxic effect Vegf Inhibitor aged base bone calcium phosphate contrast imaging design and construction early screening fluorescence imaging fluorescence lifetime imaging fovea centralis human subject imaging approach imaging modality improved in vivo in vivo imaging instrument macula novel pill response retinal imaging screening

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.

与年龄相关的黄斑变性（AMD）是发达的最常见的失明原因国家影响超过一千万美国人。疾病的发作是成绩，很少有症状，大多数患者不知道，直到通过眼睛检查检测到不可逆转的视力丧失为止。人们认为建立视网膜中脂肪和蛋白质的沉积物（其中最著名的）称为drusen，导致死亡那里的光敏细胞。虽然不太常见的AMD（CNV）的“湿”形式可以被称为毒品逮捕 VEGF抑制剂，较常见的“干”形式（GA）目前不可治疗，尽管有几种治疗方法发展。最近，我们发现drusen含有羟基石（HAP）的微观球形，A 磷酸钙在骨骼和牙齿中丰富的形式，并提出了证据，表明球形核定视网膜中drusen的生长。我们发现荧光污渍发展为研究骨骼生长还将染色球形，允许它们通过视网膜的荧光成像进行研究。我们推断，通过体内使用的这种成像方法早期检测HAP球形可能会预测 drusen的外观，从而出现AMD的发展；至少在某些情况下证实了这一点。这是这项生物工程研究赠款的作用是开发和验证视网膜成像方法为了筛查和早期检测AMD，都可以提示治疗，并遵循疾病的过程评估治疗。在动物模型中合成用于骨研究的一些污渍在体外表现良好，但它们的行为和安全性在动物中鲜为人知，根本没有人类研究。但是，有些四环素抗生素在与骨矿物质结合时也会产生明亮的荧光，我们发现它们具有在这些条件下可以从背景下解决的独特荧光寿命通过荧光寿命成像的视网膜荧光。四环素具有众所周知的行为，可以可能是口服的，在人类中非常安全。用四环素对球形图像染色我们必须构建荧光寿命成像眼镜镜（FLIO），可在人类或仅适用于AMD的好动物模型，猕猴（猴子）。我们将根据现有仪器，在供体尸体上完善我们的程序，然后对年龄进行测试和染色程序猕猴（开发球形）和一个日本猕猴，以早期和迅速发展为drusen 高脂饮食的结果。要回答的关键问题是球形的出现如何可靠 drusen和向AMD的发展的发展，以及成像程序对猴子的安全程度；令人满意的结果可能会导致人类试验。