Hedgehog Signaling in Photoreceptor Differentiation and Maintenance

光感受器分化和维护中的刺猬信号传导

• 批准号: 8197259
• 负责人: Xian-Jie Yang
• 金额: $ 36.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197259
• 关键词: Ablation; Adult; Affect; Animals; Apoptosis; Attenuated; Behavior; Bilateral; Binding; Biological Assay; Birth; Cell Cycle Progression; Cell Maintenance; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cellular Assay; Cellular Structures; Defect; Development; Electron Microscopy; Electroretinography; Embryo; Erinaceidae; Event; Genes; Genetic Recombination; Goals; Growth Factor; Homeostasis; Human; Integral Membrane Protein; Ligands; Maintenance; Mediating; Molecular; Molecular Genetics; Morphogenesis; Morphology; Mus; Nervous system structure; Neural Retina; Neurons; Outcome Study; Pattern; Photoreceptors; Play; Production; Proliferating; Protein Family; Proteins; Research; Retina; Retinal; Retinal Cone; Retinal Diseases; Retinal Ganglion Cells; Retinal Photoreceptors; Retroviridae; Role; Signal Pathway; Staging; Structure; Structure of retinal pigment epithelium; System; Testing; Tissues; Transgenic Mice; Vertebrate Photoreceptors; Visual Fields; abstracting; base; combat; extracellular; genetic analysis; human SMO protein; insight; molecular marker; mutant; nerve stem cell; novel; photoreceptor degeneration; postnatal; progenitor; receptor; recombinase; retinal neuron; retinal progenitor cell; retinal rods; retinogenesis; smoothened signaling pathway

Abstract The Hedgehog (Hh) family of proteins plays important roles in the determination of neuronal cell fates and the maintenance of adult neural stem cell potentials. Previous studies and our preliminary results indicate that Sonic hedgehog (Shh) promotes retinal progenitor cell proliferation and affects specification of early born retinal neurons. However, the precise function of Hh signaling in mammalian photoreceptor cell development and survival is not well understood. The proposed research will use molecular genetic approaches to elucidate the roles of Hh signaling during mouse photoreceptor development and maintenance. The essential Hh receptor component Smoothened (Smo) will be eliminated by Cre/loxP recombination using transgenic mouse lines and retroviruses expressing Cre recombinase. The effects of disrupting Hh signaling on postnatal progenitor proliferation and cell fate commitment, and on photoreceptor differentiation and morphogenesis will be analyzed using molecular markers and electron microscopy. The roles of Hh signaling in photoreceptor maintenance and survival will be characterized by ablating the Smo gene or the Shh gene in the mature retina followed by functional and morphological analyses. Results of the proposed research will elucidate the function of an important signaling pathway in mammalian photoreceptor differentiation and survival. Moreover, these studies will provide new insights into mechanisms of photoreceptor degeneration and opportunities to develop novel therapies for combating retinal diseases.

摘要 Hedgehog（Hh）蛋白家族在决定神经细胞命运中起着重要作用 和维持成体神经干细胞的潜能。以前的研究和我们的初步结果 表明Sonic hedgehog（Shh）促进视网膜祖细胞增殖并影响 早期视网膜神经元的特化。然而，Hh信号在哺乳动物中的确切功能 光感受器细胞的发育和存活还没有被很好地理解。该研究将使用 用分子遗传学方法阐明Hh信号在小鼠光感受器中的作用 开发和维护。基本的Hh受体成分Smoothened（Smo）将是 使用表达Cre的转基因小鼠系和逆转录病毒通过Cre/loxP重组消除 重组酶阻断Hh信号对出生后祖细胞增殖和细胞命运的影响 承诺，并对感光细胞分化和形态发生将分析使用分子 标记和电子显微镜检查。Hh信号在光感受器维持和存活中的作用 其特征在于切除成熟视网膜中的Smo基因或Shh基因， 功能和形态分析。拟议研究的结果将阐明 是哺乳动物感光细胞分化和存活的重要信号通路。此外，委员会认为， 这些研究将为光感受器退化的机制提供新的见解， 这为开发新的治疗视网膜疾病的方法提供了机会。