MEASURES OF HUMAN RECEPTOR AND POST RECEPTOR ACTIVITY

描述（由申请人提供）：我们的长期目标是开发一套用于研究人类视网膜的非侵入性技术。通过将光导的新技术和当前理论应用于全视场视网膜电图（ERG），我们成功地开发了广泛使用的无创技术来研究视杆和视锥受体以及视杆双极细胞的整体活动。这些客观视网膜功能指标可以作为系统给药治疗试验的适当结果指标。然而，许多正在进行和预期的涉及受体疾病的临床试验需要对视网膜功能进行局部测量，如多焦点ERG和静态自动视距测量，以评估治疗效果。然而，这些测试很难实施，耗时，对患者不友好，而且通常只评估锥体功能。由于视网膜成像的最新发展，我们现在可以将这些功能测量直接与底层结构联系起来。我们一直致力于一种新的无创技术，用于测量视网膜的结构（解剖），频域光学相干断层扫描（fdOCT）。这项工作得到了当前基金的支持，得益于我们新的定量方法来评估fdOCT扫描中看到的视网膜层分割。作为Aim 1的一部分，我们评估和改进了fdOCT对疾病相关光感受器损伤的测量方法，并在临床中测试了这些方法的有效性。这包括开发和评估量化fdOCT扫描的新方法。我们使用这些方法来检验关于疾病机制的假设，以及疾病进展的模型。此外，我们建议验证一个假设，即特定的fdOCT测量（即IS/OS轮廓）可以提供比目前的标准测量（如视网膜色素变性（RP））更好的疾病进展测量。作为Aim 2的一部分，我们将我们的方法扩展到黄斑疾病，这是对正常视觉功能最重要的区域。由于有证据表明黄斑病变可能首先影响视杆细胞，我们试图确定早期黄斑变性（AMD）、地理性萎缩和Stargardt病患者眼底视周测量视杆细胞功能与fdOCT测量受体完整性之间的关系。我们将检验这样的假设，即与视力或眼底摄影中萎缩面积的测量相比，杆状眼底验光和fdOCT对这些疾病的进展更敏感。目前RP和黄斑疾病进展的功能测量的固有变异性对开发有效治疗的努力具有实质性的阻碍作用。由于需要大量的患者和长时间的试验，成本变得令人望而却步。确定fdOCT在RP中的效用和有效性，以及它与黄斑疾病局部杆状和锥体介导功能测量的关系，可以大大提高未来黄斑疾病临床试验的可行性。

DESCRIPTION (provided by applicant): Our long-term objective has been to develop a set of noninvasive techniques for studying the human retina. By applying novel techniques and current theories of phototransduction to the full-field electroretinogram (ERG), we have successfully developed widely-used noninvasive techniques for studying the global activity of the rod and cone receptors, as well as the rod bipolar cells. These indices of objective retinal function can be appropriate outcome measures for treatment trials with systemically-administered agents. However, many ongoing and anticipated clinical trials involving diseases of the receptors require localized measures of retinal function, such as the multifocal ERG and static automated perimetry, for evaluating treatment efficacy. These tests, however, are difficult to administer, time consuming, and not patient friendly, plus, as typically used, assess only cone function. Due to recent developments in retinal imaging, we can now relate these functional measures directly to underlying structure. We have been focusing our efforts on a new noninvasive technique for measuring the structure (anatomy) of the retina, frequency domain optical coherence tomography (fdOCT). This work, supported by the current grant, has benefitted from our novel quantitative approaches to assessing segmentation of retinal layers seen on fdOCT scans. As part of Aim 1, we evaluate and improve our fdOCT measures of disease related damage to the photoreceptors and test the efficacy of these measures in the clinic. This includes developing and evaluating new methods for quantifying fdOCT scans. We use these methods to test hypotheses about disease mechanisms, as well as models of disease progression. In addition, we propose to test the hypothesis that a particular fdOCT measure (i.e. the IS/OS contour) can provide a better measure of disease progression than current standard measures for diseases such as retinitis pigmentosa (RP). As part of Aim 2, we extend our approach to diseases of the macula, the region of greatest importance to normal visual function. Motivated by evidence that diseases of the macula may affect the rods first, we seek to determine the relationship between fundus perimetric measures of rod function and fdOCT measures of receptor integrity in patients with early age-related macular degeneration (AMD), geographic atrophy, and Stargardt disease. We will test the hypothesis that rod fundus perimetry and fdOCT are more sensitive to progression in these diseases than visual acuity or measures of the area of atrophy on fundus photography. The inherent variability in current functional measures of progression in RP and diseases of the macula is a substantial deterrent to efforts to develop effective treatments. Costs become prohibitive due to the large numbers of patients and extensive trial durations that are required. Determining the utility and validity of fdOCT in RP, and its relationship to measures of local rod- and cone-mediated function in macular disease, could profoundly enhance the feasibility of future clinical trials in these diseases.