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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

基本信息

批准号：
8292520
负责人：
MAUREEN E NEITZ
金额：
$ 38.18万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/8292520
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

项目摘要

DESCRIPTION (provided by applicant): 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 those 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. PUBLIC HEALTH RELEVANCE: Experiments that enhance rather than ablate sensory input, such as those described in this proposal, 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. In addition, the experiments to develop less invasive methods for delivering the gene therapy vectors for retinal disease, will ultimately reduce the risks associated with treatment, making more retinal diseases accessible to this mode of therapy.

描述（由申请人提供）：这项资助申请中提出的工作的长期目标是通过增加新的感觉输入来研究成年哺乳动物视觉系统的神经可塑性，并开发腺病毒相关载体，当注射到玻璃体中时，该载体可有效地刺激视网膜细胞。增强而不是消融感觉输入的实验为回答成人视觉系统可塑性的基本问题提供了一条新的研究途径，并对基因治疗和视网膜假体的合理设计具有重要意义。可以通过注射到玻璃体中而不是注射到视网膜下腔中来递送治疗性基因的载体避免了视网膜损伤的风险，注射程序。我们选择了红-绿色色觉作为模型系统，在该模型系统中，可以使用视网膜电图和视网膜电生理学在视网膜水平上定量监测功能的获得，并且可以使用色觉、皮层生理学和功能性磁共振成像的行为测试在视觉皮层水平上定量监测功能的获得。为了实现这些目标，我们提出了两个具体目标：具体目标1。目的：研究视网膜色素和视锥细胞亚型的变化对视网膜神经节细胞和初级视皮层神经元反应的影响。为了确定接受治疗的成年人的细胞神经反应与未接受治疗的二色视者和三色视者的神经反应有何不同，这些人天生就有三种视锥细胞。确定治疗后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者的区别。具体目标2。为了确定通过玻璃体内注射携带在人L视蛋白启动子和增强子控制下的人L视蛋白基因的新一代rAAV 2载体可实现的视锥光感受器转导水平是否足以将原视（二色视）猴的色觉改变为三色视。公共卫生关系：增强而不是消融感觉输入的实验，如本提案中所述，为回答有关成人视觉系统可塑性的基本问题提供了一条新的研究途径，并对基因治疗和视网膜假体的合理设计具有重要意义。此外，开发用于提供视网膜疾病基因治疗载体的侵入性较小的方法的实验将最终降低与治疗相关的风险，使更多的视网膜疾病可以使用这种治疗模式。