Mechanisms of Vision Loss in X-Linked Juvenile Retinoschisis

X连锁青少年视网膜劈裂症视力丧失的机制

基本信息

批准号：
10386850
负责人：
James JASON McAnany
金额：
$ 46.69万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10386850
关键词：
Address Adolescent Adult Affect Age Alleles Anatomy Animal Model Atrophic Behavior Behavioral Biological Assay Blindness Cells Clinical Contrast Sensitivity Data Development Discrimination Disease Disease Progression Electrophysiology (science)Electroretinography Functional disorder Genes Goals Human Human Characteristics Immunohistochemistry Investigational Therapies Knockout Mice Lead Lesion Light Measures Mus Mutation Nature Noise Onset of illness Optical Coherence Tomography Outcome Outcome Measure Pathway interactions Patients Pattern Photoreceptors Physiological Point Mutation Process Property Proteins Psychophysics Reporting Research Rest Retina Retinal Degeneration Retinal Diseases Retinal Ganglion Cells Retinopathy of Prematurity Role Series Severities Severity of illness Signal Transduction Site Structure Study Subject Testing Time Vision Visual Visual Acuity Visual impairment X-Linked Retinoschisis XLRS1 protein base cell type clinical practice defined contribution design early onset effective therapy human disease human subject humanized mouse improved insight loss of function male mouse model mutant mutant mouse model new therapeutic target novel postnatal prevent repair strategy repaired response therapy outcome trial design visual performance visual stimulus

项目摘要

Abstract X-linked retinoschisis (XLRS), the most common cause of juvenile onset retinal degeneration in males, is characterized by cystic-appearing retinal lesions and early visual deficit. XLRS is caused by mutations in the RS1 gene that encodes the protein retinoschisin (RS1), which is expressed panretinally. Changes in retinal structure and function observed in young XLRS patients and Rs1 KO mice raise new questions regarding the role of RS1 in early XLRS pathophysiology that may impact the severity of the disease in adulthood. Questions motivated by our preliminary findings that concern the nature and extent of visual deficits in XLRS, as well as the sites and mechanisms of disease action, will be addressed in the following 3 Specific Aims. In Aims 1 and 2 we will use three Rs1 mutant mouse models, with differing levels of disease severity, to identify early retinal maladaptive changes and abnormalities associated with XLRS. In addition to a KO for Rs1, we are working with two novel ‘humanized’ mouse models that carry human disease causing Rs1 point mutations (C59S, R141C) chosen because of their distinct impacts on RS1 structure and function. In Aim 1, we will define early changes in XLRS retinal structure and function using electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT) and immunohistochemistry. Aim 2 will determine the impact of aberrant retinal function on visual discrimination and how it differs among the animal models. We then assess visually driven behavior in living mice, to determine functional metrics such as contrast sensitivity and visual acuity that are translatable to the human subjects studied in Aim 3. Together, Aims 1 and 2 will test the hypothesis that the visual deficits are directly related to early structural changes and will identify the cell type(s) that are critical to define this relationship. In Aim 3, we will use psychophysical assays to define the mechanisms that contribute to visual impairment in XLRS patients. These analyses will test the hypothesis that mutant RS1 results in behavioral abnormalities akin to those observed in the Rs1 mouse models, including reduced contrast sensitivity, elevated internal noise levels, and summation abnormalities. We anticipate the pattern of visual abnormalities to be consistent with disrupted visual maturation, as seen in other early onset retinal conditions. The completion of these Aims will greatly expand our understanding of the time course and impact of Rs1 mutations on the retina, will define the cellular basis for visual function loss in XLRS patients and will identify new therapeutic targets and outcome measures that may be more suitable for evaluating experimental therapies than SD-OCT and ERG analysis. Our findings will advance the general understanding of XLRS and how we approach and design trials of experimental therapy.

抽象的 X 连锁视网膜劈裂 (XLRS) 是男性青少年发病的视网膜变性的最常见原因，其特征是出现囊性视网膜病变和早期视力缺陷，是由 XLRS 突变引起的。 RS1 基因编码视网膜裂蛋白 (RS1)，该蛋白在全视网膜中表达。在年轻 XLRS 患者和 Rs1 KO 小鼠中观察到的结构和功能提出了关于 RS1 在早期 XLRS 病理生理学中的作用可能会影响成年后疾病的严重程度。由我们的初步发现引发的问题涉及 XLRS 视觉缺陷的性质和程度，以及疾病作用的部位和机制，将在以下 3 个具体目标中得到解决。目标 1 和 2 我们将使用三种具有不同疾病严重程度的 Rs1 突变小鼠模型来识别与 XLRS 相关的早期视网膜适应不良变化和异常除了 Rs1 的 KO 之外，我们还正在研究两种新型“人源化”小鼠模型，它们携带引起人类疾病的 Rs1 点选择突变（C59S、R141C）是因为它们对 RS1 结构和功能具有独特的影响。我们将使用视网膜电图 (ERG)、光谱来定义 XLRS 视网膜结构和功能的早期变化域光学相干断层扫描 (SD-OCT) 和免疫组织化学将确定影响。然后我们研究了异常视网膜功能对视觉辨别力的影响及其在动物模型中的差异。评估活体小鼠的视觉驱动行为，以确定功能指标，例如对比敏感度和可转化为目标 3 中研究的人类受试者的视敏度。目标 1 和 2 将一起测试假设视觉缺陷与早期结构变化直接相关，并将识别细胞对于定义这种关系至关重要的类型在目标 3 中，我们将使用心理物理学分析来定义。这些分析将检验该假设。突变的 RS1 导致行为异常，类似于在 Rs1 小鼠模型中观察到的行为异常，包括对比敏感度降低、内部噪声水平升高以及求和异常。预测视觉异常的模式与视觉成熟受到破坏一致，如这些目标的完成将极大地扩展我们对其他早发性视网膜疾病的理解。 Rs1 突变对视网膜的时间进程和影响，将确定视功能丧失的细胞基础 XLRS 患者，并将确定可能更合适的新治疗目标和结果测量与 SD-OCT 和 ERG 分析相比，我们的研究结果将促进总体治疗的评估。了解 XLRS 以及我们如何进行和设计实验治疗试验。