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: 7994779
• 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/7994779
• 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; base; combat; extracellular; genetic analysis; human SMO protein; insight; molecular marker; mutant; nerve stem cell; novel; photoreceptor degeneration; postnatal; progenitor; public health relevance; receptor; recombinase; retinal neuron; retinal progenitor cell; retinal rods; retinogenesis; smoothened signaling pathway

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The proposed research will study the influence of an important class of proteins called "hedgehog" on the formation and survival of photoreceptor cells, which undergo degeneration in various retinal diseases. The outcomes of these studies will enhance our abilities to protect photoreceptor cells and to direct the differentiation of neural stem cells towards functional photoreceptor cells for retinal disease therapy.

描述（由申请人提供）：刺猬蛋白（Hh）家族在决定神经元细胞命运和维持成体神经干细胞潜力中发挥重要作用。之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出生的视网膜神经元的规格。然而，Hh 信号在哺乳动物感光细胞发育和存活中的确切功能尚不清楚。拟议的研究将使用分子遗传学方法来阐明 Hh 信号在小鼠光感受器发育和维持过程中的作用。使用转基因小鼠品系和表达 Cre 重组酶的逆转录病毒进行 Cre/loxP 重组，可消除必需的 Hh 受体成分 Smoothened (Smo)。将使用分子标记和电子显微镜分析破坏 Hh 信号对出生后祖细胞增殖和细胞命运承诺以及光感受器分化和形态发生的影响。 Hh 信号在光感受器维持和存活中的作用将通过消除成熟视网膜中的 Smo 基因或 Shh 基因来表征，然后进行功能和形态学分析。拟议研究的结果将阐明哺乳动物光感受器分化和存活中重要信号通路的功能。此外，这些研究将为光感受器变性机制提供新的见解，并为开发治疗视网膜疾病的新疗法提供机会。 公共健康相关性：拟议的研究将研究一类被称为“刺猬”的重要蛋白质对感光细胞形成和存活的影响，感光细胞在各种视网膜疾病中会发生退化。这些研究的结果将增强我们保护感光细胞和引导神经干细胞分化为功能性感光细胞以治疗视网膜疾病的能力。