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用于研究人类视网膜的无创技术 基础科学和临床目的。通过将当前的光转移理论应用于全景 电子图（ERG），我们成功地开发了广泛使用的技术来研究全球活性 杆和锥体受体以及杆双极细胞。这些客观残留功能的指标是 适当的结局指标，用于系统管理的药物的治疗试验。但是，很多 正在进行的涉及光感受器疾病的临床试验需要进行局部测量 视网膜功能，例如多灶性电视图（MFERG），静态自动化周期（SAP）和杆 和锥介导的底面跟踪期，以评估治疗效率。随着最近的发展 视网膜成像，我们可以将视觉功能的局部视觉量与基础结构联系起来。我们有 专注于频域光学相干断层扫描（FDOCT）和眼底自动荧光（FAF）。这 在当前赠款的支持下，工作得益于我们新颖的定量方法 在FDOCT上看到的残留层的厚度与其他结构和功能措施。即将到来的重点将 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。一个主要目标是提供有关病理生理学和进展速率的见解 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（主要是视敏度和 FAF）无法在相对较短的时间间隔内用适度的样本量评估变化， 导致昂贵且漫长的临床试验。我们最近与En Face Slab Oct的工作代表了激进 RP和STGD1转化研究的变化。我们在RP中的工作几乎是独一无二的 将定量OCT作为可行的临床试验结果指标。如在Nei-FDA中所证明的 终点研讨会（NIH，2016年11月9日），对“解剖学”终点有很大的热情 irds。然而，仍有很多事情要做，将措施扩展到EZ地区并确定 外部视网膜结构改变（即EZ区域）与功能损失之间的关系。计划实验 将通过开发和评估新颖的面部来确定受体丧失的程度，性质和进展 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 和锥形，开发了将杆和锥敏感与内部和外部定量测量的模型开发的模型 分段长度，外核层厚度和内部核层厚度，并使用多模式成像 包括OCT，红外（IR）反射率和FAF在内的方法，以检验有关疾病机制和的假设 疾病进展的模型。请注意，这些实验同样适用于RP和STGD1。拍摄 总之，这些研究继续支持临床试验的新颖和更有效的结果指标。