Exploring plasticity of the adult visual system using viral gene delivery

利用病毒基因传递探索成人视觉系统的可塑性

• 批准号: 8446974
• 负责人: MAUREEN E NEITZ
• 金额: $ 39.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446974
• 关键词: Adult; Affect; Amaze; Amino Acids; Anatomy; Animals; Applications Grants; Area; Behavior; Biological Models; Blindness; Capsid; Cells; Color; Color Visions; Color blindness; Development; Dimensions; Discrimination; Dose; Electrophysiology (science); Electroretinography; Enhancers; Functional Magnetic Resonance Imaging; Functional disorder; Gene Delivery; Gene Transduction Agent; Generations; Genes; Goals; Human; Inherited; Injection of therapeutic agent; Lateral Geniculate Body; Mediating; Methods; Modeling; Monitor; Monkeys; Mus; Neuronal Plasticity; Neurons; Opsin; Pathway interactions; Pattern; Perception; Phenylalanine; Photoreceptors; Physiology; Pigments; Plastics; Primates; Procedures; Research; Retina; Retinal; Retinal Cone; Retinal Detachment; Retinal Diseases; Retinal Ganglion Cells; Risk; Sensory; Signal Transduction; Sorting - Cell Movement; Surface; System; Testing; Therapeutic; Training; Translating; Tyrosine; Ubiquitin; Visual; Visual Cortex; Visual Perception; Visual system structure; Work; adeno-associated viral vector; area striata; behavior test; critical period; design; emerging adult; functional loss; gain of function; gene therapy; improved; intravitreal injection; mature animal; neural circuit; particle; promoter; relating to nervous system; research study; response; retinal damage; retinal prosthesis; subretinal injection; therapeutic gene; tool; transduction efficiency; vector; viral gene delivery; visual deprivation; visual process; visual processing

The long-term goals of the work proposed in this grant application are to study neural plasticity of the adult mammalian visual system by adding new sensory input and to develop adeno virus associated vectors that efficiently transduce retinal cells when injected into the vitreous. Experiments that enhance rather than ablate sensory input offer a new avenue of research for answering fundamental questions about the plasticity of the adult visual system and have important implications for the rational design of gene therapy and retinal prostheses. Vectors that can deliver the therapeutic gene by injecting into the vitreous rather than into the subretinal space avoid the risk of damage to the retina from the injection procedure. We have chosen red- green color vision as a model system in which gain of function can be monitored quantitatively at the level of the retina using the electroretinogram and retinal electrophysiology and at the level of the visual cortex with behavioral tests of color vision, cortical physiology, and functional magnetic resonance imaging. Toward these goals we propose two specific aims: Specific Aim 1. To determine how changes in the photopigments and cone subtypes in the retina affect the responses of retinal ganglion cells and neurons in the primary visual cortex. To determine how the neural responses of cells in treated adults differ from untreated dichromats and trichromats that were born with three cone types. To determine the mechanism the treated monkeys use to make trichromatic color discriminations and how they differ from naturally produced trichromats. Specific aim 2. To determine whether the level of cone photoreceptor transduction achievable by intravitreal injection of new generation rAAV2 vectors carrying a human L opsin gene under control of the human L opsin promoter and enhancer is sufficient to change a protanopic (dichromatic) monkey's color vision to trichromatic.

这项研究的长期目标是研究成年人的神经可塑性 通过增加新的感觉输入，开发腺病毒相关载体， 当注射到玻璃体中时有效地抑制视网膜细胞。增强而不是消融的实验 感觉输入为回答有关大脑可塑性的基本问题提供了一条新的研究途径。 成人视觉系统，并为基因治疗和视网膜的合理设计具有重要意义 假体.可以通过注射到玻璃体中而不是注射到玻璃体中来递送治疗基因的载体 视网膜下空间避免了注射过程对视网膜造成损伤的风险。我们选择了红色- 绿色色觉作为一个模型系统，其中功能的增益可以定量监测的水平， 使用视网膜电图和视网膜电生理学以及在视觉皮层水平， 色觉、皮质生理学和功能性磁共振成像的行为测试。对这些 我们提出两个具体目标： 具体目标1.为了确定视网膜中的色素和锥细胞亚型的变化如何影响视网膜的功能， 视网膜神经节细胞和初级视皮层神经元的反应。为了确定神经系统 处理过的成年人的细胞反应与未处理的二色视者和三色视者不同， 锥类型。确定接受治疗的猴子进行三色辨色的机制 以及它们与自然产生的三色视动物有何不同。 具体目标2。为了确定通过玻璃体内注射可达到的视锥细胞转导水平， 注射携带在人L视蛋白控制下的人L视蛋白基因的新一代rAAV 2载体 启动子和增强子足以将原视（二色视）猴的色觉改变为三色视。