PHOTOTRANSDUCTION, AGING AND RETINAL DEGENERATION

光传导、衰老和视网膜变性

• 批准号: 6346479
• 负责人: MELVIN SIMON
• 金额: $ 13.49万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-02-10 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6346479
• 关键词: Mammalia; aging; apoptosis; arrestins; biological information processing; biological signal transduction; gene expression; gene mutation; genetic mapping; genetic promoter element; genetically modified animals; guanosinetriphosphatases; intermolecular interaction; laboratory mouse; phosphorylation; retina degeneration; rhodopsin kinase; tissue /cell culture; visual photoreceptor; visual phototransduction

The mammalian visual system provides an excellent opportunity to understand how biological information processing systems operate in vivo and how they integrate with other cellular functions. Our long term goals are: (1) To understand the steps and biochemical mechanisms that operate in vivo to regulate and maintain the extraordinary performance characteristics of the phototransduction cascade in mammalian photoreceptors. (2) We want to understand how changes in the phototransduction circuit generate signals that induce cell death (apoptosis) and eventually retinal degeneration. A variety of age related, late onset retinal diseases are the result of apoptotic signaling and neural degeneration. Genetic modifications of components of the visual system provide models to study these effects and to evaluate gene therapy and pharmaceutical approaches designed to block apoptotic signaling in order to delay damage and prevent cell death in photoreceptors. In the next few years our laboratory will focus on developing multiple mutations and combinations of mutants and ectopic gene expression by breeding and by generating new genetic constructs designed to answer specific questions about the photocascade and about retinal degeneration. Some of our specific short term goals are: (1) To determine the nature of the factors that accelerate the GTPase activity of visual transducin. Is the RGS9 protein specifically involved in the rapid termination of the transducin mediated signal in vivo? Is RGS9 alone sufficient to account for this "turn off"? What is the nature of the molecular interactions of RGS with transducin? (2) To understand the molecular basis for rapid "turn off" and reactivation that we observe in Rhodopsin Kinase deficient photoreceptors. (3) We will focus on the mechanisms that are required to generate light induced signals that lead to apoptosis, particularly in Rhodopsin Kinase and Arrestin deficient mice; (4) We will try to determine the in vivo role of other gene products involved in the dephosphorylation and the recycling of Rhodopsin during the photocascade and examine how they might be involved in inducing apoptosis; (5) We will continue to study the effects of deletion or overexpression of genes that are involved in apoptotic signaling or in blocking apoptosis under conditions that ordinarily lead to retinal degeneration.

哺乳动物视觉系统为 了解生物信息处理系统如何在体内运行 以及它们如何与其他细胞函数集成。我们的长期 目标是：（1）了解步骤和生化机制 在体内操作以调节和维持非凡的性能 哺乳动物中光转导级联的特征 感受器。 （2）我们想了解如何变化 光转导回路产生诱导细胞死亡的信号 （凋亡），最终视网膜变性。 多种年龄 相关的，晚期视网膜疾病是凋亡的结果 信号传导和神经变性。 组件的遗传修饰 视觉系统提供了研究这些效果的模型和 评估旨在阻止的基因疗法和药物方法 凋亡信号传导以延迟损害并防止细胞死亡 感受器。 在接下来的几年中，我们的实验室将专注于发展多个 突变体和异位基因表达的突变和组合 繁殖并产生旨在回答的新遗传结构 有关影印器和视网膜的具体问题 退化。 我们的一些特定短期目标是：（1） 确定加速GTPase活性的因素的性质 视觉传统。 RGS9蛋白是特别参与的 经体在体内介导的信号的快速终止？ 是RGS9 一个人足以说明这种“关闭”吗？ 什么是什么 RGS与转霉素的分子相互作用？ （2）了解 我们观察到的快速“关闭”和重新激活的分子基础 在视紫红质激酶缺乏的光感受器中。 （3）我们将专注于 生成引导信号所需的机制 凋亡，特别是在视紫红质激酶和阻止蛋白缺乏的情况下 小鼠； （4）我们将尝试确定其他基因的体内作用 涉及去磷酸化和回收的产品 在影印过程中的视紫红质，并检查它们如何参与 诱导凋亡； （5）我们将继续研究 与凋亡有关的基因的缺失或过表达 信号传导或阻塞凋亡在通常导致的条件下 视网膜变性。