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) 是高度特化的细胞，可将光能转换成有用的生理信号。 在脊椎动物中，睫状体、视杆细胞和视锥细胞启动视觉。杆和锥的经典定义是 基于外节的形态，一种富含膜的细胞器，专门用于捕获 光及其处理，以便向其他视网膜神经元发出信号。 PR 的光强度范围 运作也是其定义的一个基本方面，视杆细胞在昏暗的光线下运作，视锥细胞在较亮的光线下运作 光。视锥细胞启动我们的颜色和高敏锐度视觉，视锥细胞进一步由波长敏感性定义 他们的视蛋白。尽管我们非常重视我们的视觉，特别是我们的视觉敏锐度颜色 视觉方面，我们对视锥细胞在发育过程中是如何产生的知之甚少。这些信息将有助于 当它们在许多类型的导致失明的疾病中失败时，进行替代它们的努力。目前的干细胞 锥体生产的方法非常有限，主要是由于缺乏对正常锥体生产的了解。 发展线索。这些方法需要新的策略来产生足够的视锥细胞，使其成为 有效的治疗。 除了治疗应用的益处外，PR 发生机制的知识 将帮助我们了解这一类重要的感觉神经元的进化和发展。 鉴于愿景的高价值，公关人员面临着沉重的选择压力。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来模糊视杆和视锥的定义。在 此外，不同物种之间的视杆细胞分布和不同类型的视杆细胞也存在显着差异。 穿过视网膜的视锥细胞。例如，在人类中，有一个小的高敏锐度区域，即中央凹，视锥细胞位于此处 唯一的公关类型。了解如何确定视杆细胞和视锥细胞将有助于理解 导致这些模式、形态和生理差异的一些机制 跨物种。 这笔赠款的重点将是视锥细胞在发育过程中如何选择它们的命运的问题，利用 基因组数据和现代方法。出发点是定义两个基因的转录调控 视锥发生所需的关键基因 Otx2 和 Oc1 以及 Notch1 控制下的下游事件 最早已知的锥体发生调节因子，然后利用这些数据推导锥体基因调节 网络。