Measures of Human Receptor and Post Receptor Activity

人类受体和受体后活性的测量

• 批准号: 9789314
• 负责人: DAVID G BIRCH
• 金额: $ 63.66万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789314
• 关键词: Affect; Age related macular degeneration; Anatomy; Area; Basic Science; Blindness; Cells; Clinical; Clinical Trials; Cone; DNA Sequence Alteration; Development; Disease; Disease Progression; Disease model; Educational workshop; Effectiveness; Electroretinography; Eye; Foundations; Frequencies; Functional disorder; Fundus; Gene Transduction Agent; Genes; Goals; Grant; Health; Human; Image; Inner Nuclear Layer; Internet; Kinetics; Length; Localized Disease; Measures; Mediating; Methods; Modeling; Molecular; Monitor; Multimodal Imaging; Mutation; Natural History; Nature; Nerve Fibers; Nuclear; Ophthalmologist; Optical Coherence Tomography; Optics; Outcome Measure; Patients; Perimetry; Photoreceptors; Phototransduction; Receptor Cell; Retina; Retinal; Retinal Cone; Retinal Diseases; Sample Size; Scanning; Source; Stargardt' s disease; Structural defect; Structure; Structure-Activity Relationship; Techniques; Testing; Thick; Translational Research; Treatment Efficacy; United States National Institutes of Health; Vertebrate Photoreceptors; Vision; Visual Acuity; Visual Fields; Width; Work; alternative treatment; cohort; design; disease-causing mutation; experimental study; fighting; functional loss; imaging modality; indexing; inherited retinal degeneration; insight; novel; primary outcome; receptor; recruit; retinal imaging; retinal rods; success; theories; time interval; tomography; treatment trial; virtual; willingness

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.

我们的长期目标是开发非发育的无创技术来研究人类视网膜 基础科学和临床目的。 电子图（ERG），我们成功地开发了用于研究全球活动的技术 杆和锥体受体以及杆双极细胞。 适用于系统性管理剂的治疗试验的适当结果指标。 持续和预期的光感受器的临床试验疾病需要局部措施 视网膜功能，例如多灶性电谱图，静态自动化（SAP）和杆 随着最近的发展和锥体介导的底底跟踪外的发展，以评估治疗功效。 视网膜成像，我们可以将视觉功能的局部度量与我们的基础结构联系起来 专注于明天的自由域光学连贯性（FDOCT）和底面自动荧光（FAF） 在当前赠款的支持下，工作得益于我们的新颖定量方法 在FDOCT上看到的视网膜层的厚度到即将到来的其他结构和功能措施。 对具有遗传性遗传的遗传性视网膜变性（IRD）的患者（包括STGD1） 突变。 通过我们的新型成像和功能测量，分子表征了患者。 RP（主要是SAP和ERG）和STGD1（初始视力和敏锐度和 faf）无法评估变化的样本量超过 导致昂贵且漫长的临床试验。 在RP和STGD1中的转化研究的变化。 将定量OCT作为可行的临床试验结果指标建立定量。 端点研讨会（NIH，2016年11月9日），对“解剖学”终点的热情非常热情 irds。 外部视网膜结构改变（即EZ区域）与功能损失之间的关系。 将通过开发和评估新颖的面部来确定受体丧失的程度，自然和进步 用于量化广场OCT扫描的受体区域的平板方法，将OCT参数与杆有关 和锥汁，开发与棒和锥敏感性与定量与内部和外部定量度量相关的模型 段长度，外核层t一些 包括OCT，红外（IR）反射率和FAF检验假设的方法有关疾病机制和 疾病计划的模型。这些实验适用于RP和STGD1 这些研究一起继续支持临床试验的新颖和更效率的结果指标。