Determination of Cone Photoreceptor Fate

视锥细胞命运的测定

• 批准号: 10539248
• 负责人: CONSTANCE L CEPKO
• 金额: $ 41.66万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539248
• 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; 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; 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，其将光能转化为有用的生理信号。 在脊椎动物中，睫状体PR、视杆细胞和视锥细胞启动视觉。视杆细胞和视锥细胞的经典定义是 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。光强度的范围超过PR 视杆细胞在昏暗的光线下工作，视锥细胞在明亮的光线下工作， 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opsin。尽管我们高度重视我们的视力，特别是我们的高灵敏度颜色 视觉，我们对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 当它们在许多导致失明的疾病中失效时，当前干细胞 方法是非常有限的，在锥生产，主要是由于缺乏知识的正常 发展线索这些方法需要新的策略来产生足够的视锥细胞， 有效的治疗。 除了对治疗应用的益处外，PR发生机制的知识 将为我们理解这类重要的感觉神经元的进化和发展提供信息。 鉴于视力的高价值，PR面临着巨大的选择压力。这导致了各种各样的 PR类型，使用经典定义的形态学和生理学模糊了视杆细胞和视锥细胞的定义。在 此外，不同种类的杆状物的分布和不同类型的 视网膜上的视锥细胞例如，在人类中，有一个小的高敏锐度区域，即中央凹，视锥细胞在那里。 唯一的PR类型了解视杆细胞和视锥细胞是如何决定的， 驱动这些模式、形态和生理差异的一些机制 跨越物种。 这项资助的重点将是锥细胞在发育过程中如何选择命运的问题， 基因组数据和现代方法。我们的出发点将是确定两个转录调控 球果发生所需的关键基因Otx2和Oc1，以及Notch1控制的下游事件， 最早已知的调节子的锥发生，然后使用这些数据来推导锥基因调控 网络。