Determination of Cone Photoreceptor Fate

视锥细胞命运的测定

• 批准号: 10320020
• 负责人: CONSTANCE L CEPKO
• 金额: $ 40.41万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320020
• 关键词: Afferent Neurons; Area; Binding Sites; Blindness; Cells; Chick; Chromatin Structure; Classification; Color; Color Visions; Complex; Cone; Cues; Data; Data Set; Development; Disease; Event; Evolution; Gene Expression; Genes; Genetic Transcription; Grant; Human; Knowledge; Lead; Light; Mediating; Membrane; Methodology; Methods; Modeling; Modernization; Morphology; Mus; NOTCH1 gene; Natural regeneration; Opsin; Organelles; Pattern; Photoreceptors; Phototransduction; Physiological; Physiology; Production; RNA; Regulation; Retina; Retinal Cone; Rod; Signal Transduction; Suggestion; Testing; Therapeutic; Transcriptional Regulation; Vertebrate Photoreceptors; Vertebrates; Vision; Zebrafish; base; cell type; cellular transduction; effective therapy; flexibility; fovea centralis; gene regulatory network; genetic manipulation; genomic data; light intensity; pressure; rapid technique; retinal neuron; stem cells; transcription factor

Photoreceptors (PRs) are highly specialized cells that transduce light energy into useful physiological signals. In vertebrates, the ciliary PRs, rods and cones, initiate vision. The classical definition of rods and cones is based upon the morphology of the outer segment, a membrane rich organelle specialized for the capture of light and its processing so as to signal other retinal neurons. The range of light intensities over which PRs operate is also a fundamental aspect of their definition, with rods operating in dim light and cones in brighter light. Cones initiate our color and high acuity vision, with cones further defined by the wavelength sensitivity of their opsin. Despite the high value we place on our vision, particularly our conemediated high acuity color vision, we know very little about how cones are generated during development. This information would aid in the efforts to replace them when they fail in many types of diseases leading to blindness. Current stem cell methods are very limited in cone production, principally due to a lack of knowledge regarding the normal developmental cues. New strategies are needed for these methods to produce enough cones to make this an effective therapy. In addition to the benefits for therapeutic applications, knowledge of the mechanisms of PR genesis would inform our understanding of the evolution and development of this important class of sensory neurons. Given the high value of vision, PRs are under heavy selective pressure. This has resulted in a wide variety of PR types, with a blurring of rod and cone definition using classically-defined morphology and physiology. In addition, there are dramatic differences among species in the distribution of rods and the different types of cones across the retina. For example, in humans, there is a small high acuity area, the fovea, where cones are the only PR type. An understanding of how rods and cones are determined would allow for an appreciation of some of the mechanisms that have driven these patterning, morphological, and physiological differences across species. The focus of this grant will be the question of how cones choose their fate during development, utilizing genomic data and modern methodologies. The starting point will be to define the transcription regulation of two key genes required for cone genesis, Otx2 and Oc1, and the downstream events under control of Notch1, the earliest known regulator of cone genesis, and then use these data to derive the cone gene regulatory network(s).

光感受器（PR）是高度专业的细胞，可将光能转化为有用的生理信号。 在脊椎动物中，睫状PR，杆和锥体启动视力。杆和锥的经典定义是 基于外部段的形态，一种富含膜的细胞器，专门用于捕获 光及其加工以发出其他视网膜神经元的信号。 PRS的光强度范围 操作也是其定义的基本方面 光。圆锥体启动我们的颜色和高敏度视觉，锥体进一步定义 他们的行动。尽管我们在视觉上具有很高的价值，尤其是我们的高敏锐颜色 视觉，我们对开发过程中锥的产生方式知之甚少。这些信息将有助于 当它们失败的许多类型的疾病导致失明时，替换它们的努力。当前的干细胞 方法的锥体生产非常有限，主要是由于缺乏有关正常的知识 发展线索。这些方法需要新的策略来生产足够的锥体以使其成为 有效的疗法。 除了对治疗应用的益处，知识PR Genesis机制 将告知我们对这一重要的感觉神经元的进化和发展的理解。 鉴于视觉的高价值，PR在重选择压力下。这导致了各种各样的 PR类型，使用经典定义的形态和生理学的杆和锥定义模糊。在 此外，杆分布和不同类型的不同类型的物种之间存在巨大差异 横跨视网膜的锥。例如，在人类中，有一个很小的高敏锐区域，即圆锥形的中央凹处 唯一的公关类型。了解如何确定杆和锥体将允许对 驱动这些图案，形态学和生理差异的一些机制 跨物种。 这笔赠款的重点将是锥体在开发过程中如何选择其命运的问题 基因组数据和现代方法论。起点是定义两个的转录调节 锥发生，OTX2和OC1所需的关键基因，以及在Notch1控制下的下游事件， 最早已知的锥发生调节剂，然后使用这些数据来得出锥体基因调节 网络。