Measures of Human Receptor and Post Receptor Activity

我们的长期目标是开发非侵入性技术来研究人类视网膜 既有基础科学，也有临床用途。通过将当前的光传导理论应用于全场 视网膜电信号(ERG)，我们成功地开发了广泛使用的技术来研究全球活动 视杆和视锥受体，以及视杆双极细胞。这些客观视网膜功能的指标是 系统给药药物治疗试验的适当结果衡量标准。然而，许多人 正在进行的和预期的涉及光感受器疾病的临床试验需要本地化措施 视网膜功能，如多焦视网膜电图(MfERG)、静态自动视野检查(SAP)和视杆 以及视锥细胞介导的眼底追踪视野检查，以评估治疗效果。随着最近的发展， 通过视网膜成像，我们可以将视功能的局部测量与潜在结构联系起来。我们有 重点是频域光学相干断层扫描(FdOCT)和眼底自发荧光(Faf)。这 在目前赠款的支持下，我们的工作受益于我们新的量化方法 FdOCT上所见的视网膜层厚度与其他结构和功能指标比较。即将到来的焦点将是 适用于遗传性视网膜变性(IRD)患者，包括STGD1，具有确定的基因 突变。一个主要的目标是提供对病理生理学和进展率的洞察力。 用我们新的成像和功能测量方法对患者进行分子特征分析。 目前在RP(主要是SAP和ERG)和STGD1(主要是视力和ERG)方面的结果测量 FAF)不能在相对较短的时间间隔内以适度的样本大小评估变化， 导致昂贵和冗长的临床试验。我们最近对EN面板OCT的研究代表了一个激进的 RP和STGD1中翻译研究的变化。我们在RP中的工作实际上是独一无二的，因为我们 将建立定量OCT作为一种可行的临床试验结果衡量标准。根据NEI-FDA的证据 Endents研讨会(NIH，2016年11月9日)，人们相当热衷于为 红斑狼疮。然而，要将这些措施扩大到EZ地区，并建立 视网膜外结构改变(即EZ区)与功能丧失的关系计划中的实验 将通过开发和评估新的面对面来确定受体丢失的程度、性质和进展 将OCT参数与视杆相关的广场OCT扫描感受器区域量化的平板方法 和锥体SAP，开发了杆和锥体敏感性与内外定量测量之间的关系的模型 分段长度、外核层厚度和内核层厚度，并使用多模式成像 方法包括OCT、红外(IR)反射率和FAF来检验关于疾病机制和疾病的假说 疾病发展的模型。请注意，这些实验同样适用于RP和STGD1。已被占用 总之，这些研究继续支持临床试验的新的和更有效的结果衡量标准。

Our long-term objective has been to develop noninvasive techniques for studying the human retina for both basic science and clinical purposes. By applying current theories of phototransduction to the full-field electroretinogram (ERG), we successfully developed widely used 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 are appropriate outcome measures for treatment trials with systemically administered agents. However, many ongoing and anticipated clinical trials involving diseases of the photoreceptors require localized measures of retinal function, such as the multifocal electroretinogram (mfERG), static automated perimetry (SAP), and rod and cone-mediated fundus tracking perimetry, for evaluating treatment efficacy. With recent developments in retinal imaging, we can relate localized measures of visual function to the underlying structure. We have focused on frequency domain optical coherence tomography (fdOCT) and fundus autofluorescence (FAF). This work, supported by the current grant, has benefitted from our novel quantitative approaches for relating the thickness of retinal layers seen on fdOCT to other structural and functional measures. The upcoming focus will be on patients having Inherited Retinal Degenerations (IRDs), including STGD1, with identified genetic mutations. A primary goal is to provide insights into the pathophysiology and rates of progression in molecularly characterized patients with our novel imaging and functional measures. Present outcome measures in RP (primarily SAP and ERGs), and STGD1 (primarily visual acuity and FAF) are incapable of assessing change with modest sample sizes over a relatively short time interval, resulting in expensive and lengthy clinical trials. Our recent work with en face slab OCT represents a radical change in translational research in RP and STGD1. Our work in RP is virtually unique in the steps we are taking to establish quantitative OCT as a viable clinical trial outcome measure. As evidenced at the NEI-FDA endpoints workshop (NIH, Nov 9, 2016), there is considerable enthusiasm for an “anatomical” endpoint for IRDs. Nevertheless, there is still much to be done to expand the measures to EZ area and to establish the relationship between outer retinal structural alterations (i.e. EZ area) and functional loss. Planned experiments will determine the extent, nature and progression of receptor loss by developing and evaluating novel en face slab methods for quantifying the receptor regions on wide-field OCT scans, relating OCT parameters to rod and cone SAP, developing models relating rod and cone sensitivity to quantitative measures of inner and outer segment length, outer nuclear layer thickness, and inner nuclear layer thickness, and using multimodal imaging methods including OCT, infrared (IR) reflectance and FAF to test hypotheses about disease mechanisms and models of disease progression. Note that these experiments apply equally to RP and to STGD1. Taken together, these studies continue to support novel and more efficient outcome measures for clinical trials.