Mechanisms of Ocular Development

眼部发育机制

• 批准号: 8076537
• 负责人: THOMAS T NORTON
• 金额: $ 4.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-04-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076537
• 关键词: Adolescent; Affect; Animal Model; Animals; Biological Assay; Blindness; Child; Choroid; Choroidal Neovascularization; Complex; Contact Lenses; Cues; Darkness; Dissociation; Drug Design; Event; Extracellular Matrix; Eye; Eye Development; Fibroblasts; Funding; Future; Gene Expression; Genes; Glass; Glaucoma; Goals; Growth; Human; Image; Individual; Intervention; Knowledge; Laboratories; Lead; Learning; Length; Messenger RNA; Methods; Molecular; Myopia; Newborn Infant; Operative Surgical Procedures; Ophthalmic examination and evaluation; Optics; Pathway interactions; Pattern; Photoreceptors; Population; Primates; Proteins; Proteomics; Recording of previous events; Relative (related person); Research; Research Design; Retina; Retinal; Retinal Detachment; Risk; Sclera; Shapes; Signal Pathway; Signal Transduction; Source; Stimulus; Structure of retinal pigment epithelium; Technology; Testing; Time; Travel; Tupaiidae; Visual; Work; base; cost; deprivation; design; emmetropization; experience; gel electrophoresis; lens; mRNA Expression; novel; postnatal; prevent; programs; protein expression; public health relevance; research study; response; retinal neuron; tool; visual stimulus

DESCRIPTION (provided by applicant): Newborn and juvenile eyes have an emmetropization mechanism that uses visual signals to precisely adjust the axial length of the eyes to the optical power, so that images are in sharp focus. However, nearly 30% of the U.S. population develops axial myopia, in which the eyes are elongated relative to the focal plane. Although glasses, contact lenses and refractive surgery can provide an optical correction, the increased axial length of the eye significantly raises the risk of retinal detachment, choroidal neovascularization and glaucoma, making myopia the 7th leading cause of blindness in the U.S. The emmetropization mechanism has at least three main components: 1) the retina, which responds to the sign and amount of defocus (or other visual cues); 2) a signaling cascade that originates in the retina, travels through the retinal pigment epithelium (RPE) and choroid, and reaches the sclera (the fibrous outer coat of the eye); and 3) fibroblasts in the sclera which respond to the signaling cascade by regulating the axial length. Our working hypothesis is that retinal responses to visual stimuli control the remodeling of the scleral extracellular matrix and, in particular, the slippage of the layers (lamellae) of the sclera across each other. This, in turn, controls scleral extensibility, axial elongation, and refractive state. The proposed studies will examine the retinal responses to visual stimuli and the scleral responses to the signaling cascade. In the previous project period, we identified two novel "dissociation" paradigms in which similar visual stimuli produce different scleral responses due to the prior history of the eye (somewhat longer or shorter than normal, an "eye-size" factor). Specific Aims 1 and 2 will use these dissociative paradigms to test our hypothesis that the source of this variability is localized in the patterns of gene expression in the sclera, rather than in the retina, and to identify the specific scleral signaling pathways that are involved. Specific Aim 3 will use an "association" paradigm in which three different methods (darkness, form deprivation, and minus-lens wear) will be used to induce myopia to identify the pattern of retinal gene expression that is common to all three and contributes to the "retina go" response. The proposed studies will apply proteomic tools and our "Pathway-focused PCR Assay" that have been developed in this laboratory to assess retinal mRNA and protein-expression patterns that characterize retinal go and retina stop responses, and scleral mRNA and protein-expression patterns that characterize the sclera go, sclera stop and sclera ignores responses in our well-characterized animal model, tree shrew. These animals are closely related to primates and, like humans, have an all-fibrous sclera. These studies will enhance our understanding the emmetropization mechanism at the level of gene expression and may lead to successful optical or pharmacological interventions to slow or prevent myopia. PUBLIC HEALTH RELEVANCE Myopia (nearsightedness) affects over 25% of the U.S. population and perhaps one billion people worldwide. In addition to the cost (over $14 billion annually) of eye exams, glasses, contact lenses, and refractive surgery, even low amounts of myopia raise the risk of developing blinding conditions. This application will identify genes and gene products that control the axial length of the eye as a step toward finding ways to prevent or minimize myopia in children.

描述（由申请人提供）：新生儿和少年眼具有一种弹性化机制，该机制使用视觉信号来精确地将眼睛的轴向长度调整为光学功率，以使图像焦点焦点。但是，近30％的美国人群发展出轴向近视，其中相对于焦平面而言，眼睛伸长。尽管眼镜，隐形眼镜和屈光手术可以提供光学校正，但轴向长度的增加显着增加了视网膜脱离，脉络膜新生血管形成和青光眼的风险，使近视成为美国失明的第7个主要原因。 2）一个起源于视网膜的信号传导级联反应，穿过视网膜色素上皮（RPE）和脉络膜，并到达巩膜（眼睛的纤维外涂层）； 3）巩膜中的成纤维细胞通过调节轴向长度来响应信号级联反应。我们的工作假设是，视网膜对视觉刺激的反应控制着巩膜外基质的重塑，尤其是巩膜的层（薄片）彼此之间的滑动。反过来，这控制了巩膜的可扩展性，轴向伸长和折射状态。拟议的研究将检查对视觉刺激的视网膜反应以及对信号级联反应的巩膜反应。在上一个项目时期，我们确定了两个新颖的“解离”范式，其中类似的视觉刺激由于眼睛的先前历史而产生不同的硬化反应（比正常人更长或短，是“眼睛大小”因子）。具体目的1和2将使用这些解离范式来检验我们的假设，即这种可变性的来源位于巩膜中的基因表达模式中，而不是在视网膜中，并识别涉及的特定巩膜信号传导途径。特定的目标3将使用“关联”范式，在这种范式中，将使用三种不同的方法（黑暗，形式的剥夺和负镜头磨损）来诱导近视，以识别这三种标志性基因表达的模式，这些模式是所有三种共有的，并有助于“视网膜GO”反应。 The proposed studies will apply proteomic tools and our "Pathway-focused PCR Assay" that have been developed in this laboratory to assess retinal mRNA and protein-expression patterns that characterize retinal go and retina stop responses, and scleral mRNA and protein-expression patterns that characterize the sclera go, sclera stop and sclera ignores responses in our well-characterized animal model, tree shrew.这些动物与灵长类动物密切相关，并且像人类一样具有全纤维巩膜。这些研究将增强我们在基因表达水平上的弹性化机制的理解，并可能导致成功的光学或药理干预措施减慢或预防近视。公共卫生相关性近视（近视）影响了美国人口的25％，在全球范围内也许有十亿人口。除了眼睛检查，眼镜，隐形眼镜和屈光手术的成本（每年超过140亿美元）外，即使近视量也很少，也增加了患有盲目状况的风险。该应用将确定控制眼睛轴向长度的基因和基因产物，这是寻找预防或最小化儿童近视的方法的一步。