Cross Sectional Cataract Study with the NASA Dynamic Lig

使用 NASA 动态 Lig 进行白内障横截面研究

• 批准号: 7322369
• 负责人: Manuel B Datiles
• 金额: --
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7322369
• 关键词: Cross; Sectional; Cataract; Study; NASA

Cataracts are the foremost cause of blindness in the world and currently can be treated only by surgical removal. Surgery, although easily available and safely performed in the U.S., is not easily available nor safely performed in many undeveloped regions in the world like Asia, Africa, the Middle East and South America. Hence we are studying ways to treat cataract using medical (non surgical) treatment. One principal theory on the cause of cataracts is that the crystallin proteins inside the lens clump together to form high molecular weight "aggregates" that scatter light and cause clouding of the lens. This can be due to overwhelming external stresses or failure of internal protective systems to work. We are working on a new technology that will help us find out what happens to the lens tissues that may lead to cataracts, and therefore help us find a cure for cataracts. It will also help determine if new potential anti cataract drugs do work in patients, since it can detect progression or regression of the cataract early on. This technology is based on Dynamic Light Scattering or DLS, that can detect molecular interactions, including lens crystallin protein interactions that occur in the lens of a living patient. This technology sorts out particle size, shape and interactions based on the brownian movement of these particles inside the living eye. First using the new DLS probe on animal models of cataract, we indeed found lens protein aggregation as a cataract initially develops. These studies showed the DLS's potential to detect the earliest changes occurring in cataract, at the stage where anti cataract treatment would theoretically be most effective in reversing, delaying or preventing cataracts. In collaboration with Drs. Ansari and Suh of NASA's John Glenn Center in Cleveland, Ohio, we developed a new miniaturized clinical version of this device for use on patients, modifying it using feedback from our patients in a preliminary study. We mounted the DLS probe successfully on the Keratoscope, a clinical device used by cornea surgeons to map the cornea, which has a 3-D aiming system to enhance repeatability. We then conducted a pilot study on 15 normal human volunteers (Phase 1) to test the safety, usefulness and reproducibility of this instrument for quantitating lens changes, and found good reproducibility. We also derived the mean log particle size (derived from particle size distribution) to be used as the preferred parameter to use for our data. In the current Phase 2 of this project, we successfully recruited and studied 250 patients in a cross sectional study to determine the clinical changes in the human lens in vivo due to aging (age related changes), as well as molecular changes found in the three main types of cataracts (nuclear, cortical and PSC). Each patient underwent a complete comprehensive eye examination, cataract clinical grading, photography of the cataract (followed by grading of the photograph by a Reading Center), and finally testing with the Clinical DLS device. All patients in this NEI-IRB approved study gave their full informed consent. We found that with normal aging, there is a slow but continuous loss of the small protein group, and continuous increase high molecular weight lens proteins. During cataract formation, we observed first a slow decrease, followed by loss of the low molecular weight proteins. Concurrently, there was a dramatic increase in high molecular weight proteins, so that in a cataract (such as an AREDS Clinical Stage 2.5 nuclear cataract), all the lens proteins formed a large molecular weight grouop or even a single peak in many cases. In some cortical and posterior subcapsular cataracts, there are marked molecular changes in the lens nucleus even when the nucleus remains clear and does not seem to be affected. It worth pointing out that previously, these in vivo, non invasive lens aging and cataract studies were not even possible because we had no way to detect and measure these early lens and cataract changes in the molecular level. This new technology offers a new, sensitive and precise method to study conditions and medications that can either cause cataract or prevent cataract. Statistical analysis of the data showed excellent correlation between DLS data and Clinical and photographic Lens Grading data, demonstrating the validity of the system in detecting and measuring cataractous change. The data also showed good reproducibility (less than 5% error). This study shows that the DLS method can detect and measure the severity of clouding of the lens (cataract) objectively, making it useful in field as well as remote studies such as in monitoring astronauts for cataract in outer space. The development of this technique will help us conduct future clinical cataract studies of all sorts, with great sensitivity and accuracy. This technology will help us to better understand the underlying causes of cataracts and help us develop and test new treatments to delay, reverse or prevent cataract formation such as the National Eye Institute's Tempol H eye drops which was recently developed.

白内障是世界上最主要的致盲原因，目前只能通过手术切除来治疗。手术，虽然在美国很容易获得和安全地进行，在世界上许多不发达地区，如亚洲、非洲、中东和南美洲，因此，我们正在研究使用药物（非手术）治疗白内障的方法。 关于白内障原因的一个主要理论是，透镜内的晶状体蛋白聚集在一起形成高分子量“聚集体”，其散射光并导致透镜混浊。这可能是由于巨大的外部压力或内部保护系统无法工作。我们正在研究一种新技术，它将帮助我们发现可能导致白内障的透镜组织发生了什么变化，从而帮助我们找到治疗白内障的方法。它还将有助于确定新的潜在抗白内障药物是否对患者有效，因为它可以早期检测白内障的进展或消退。 该技术基于动态光散射或DLS，其可以检测分子相互作用，包括在活体患者的透镜中发生的透镜晶状体蛋白质相互作用。这项技术根据这些粒子在活体眼睛内的布朗运动，对粒子的大小、形状和相互作用进行分类。 首先在白内障动物模型上使用新的DLS探针，我们确实发现了白内障最初发展时的透镜蛋白聚集。这些研究表明，DLS有潜力检测白内障发生的最早变化，在这个阶段，抗白内障治疗理论上最有效地逆转、延迟或预防白内障。 我们与位于俄亥俄州克利夫兰的美国宇航局约翰格伦中心的安萨里和苏博士合作，开发了一种新的小型临床版本的这种设备，用于患者，并在初步研究中利用患者的反馈对其进行了修改。我们成功地将DLS探头安装在角膜镜上，角膜镜是角膜外科医生用于绘制角膜的临床设备，具有3-D瞄准系统以提高可重复性。 然后，我们对15名正常人类志愿者进行了初步研究（第1阶段），以测试该仪器用于定量透镜变化的安全性、有用性和重现性，并发现良好的重现性。我们还推导出平均对数粒度（来自粒度分布），用作我们数据的首选参数。 在该项目的当前第2阶段，我们成功招募并研究了250名患者，进行了一项横断面研究，以确定人体透镜因老化（年龄相关变化）而在体内发生的临床变化，以及在三种主要类型的白内障（核性、皮质性和PSC）中发现的分子变化。每例患者均接受了完整的综合眼科检查、白内障临床分级、白内障摄影（随后由阅读中心对照片进行分级），最后使用临床DLS器械进行测试。在这项NEI-IRB批准的研究中，所有患者都提供了完全知情同意书。 我们发现，随着正常老化，存在缓慢但持续的小蛋白质组的损失，和持续增加的高分子量透镜蛋白。在白内障形成过程中，我们首先观察到低分子量蛋白质的缓慢减少，然后是损失。同时，高分子量蛋白质急剧增加，因此在白内障（如AREDS临床阶段2.5核性白内障）中，所有透镜蛋白质形成大分子量组，或在许多情况下甚至形成单峰。在某些皮质性和后囊下白内障中，即使核保持清晰且似乎未受影响，透镜核也有明显的分子变化。 值得指出的是，以前，这些体内、非侵入性的透镜老化和白内障研究甚至是不可能的，因为我们没有办法在分子水平上检测和测量这些早期透镜和白内障的变化。这项新技术提供了一种新的，敏感和精确的方法来研究可能导致白内障或预防白内障的条件和药物。 数据的统计分析显示DLS数据与临床和摄影透镜分级数据之间具有良好的相关性，证明了该系统在检测和测量白内障变化方面的有效性。数据还显示出良好的再现性（小于5%的误差）。 这项研究表明，DLS方法可以客观地检测和测量透镜混浊（白内障）的严重程度，使其在现场以及远程研究，如在监测宇航员的白内障在外层空间。这项技术的发展将有助于我们进行未来的各种临床白内障研究，具有很高的灵敏度和准确性。这项技术将帮助我们更好地了解白内障的根本原因，并帮助我们开发和测试新的治疗方法，以延迟，逆转或预防白内障的形成，如国家眼科研究所最近开发的Tempol H滴眼液。