Photoreceptor degeneration and rescue in zebrafish

描述（由申请人提供）：我们已经鉴定了一种盲斑马鱼突变体，其由于视锥磷酸二酯酶c（pde6c）基因（视锥光转导中的关键调节组分）突变而导致视锥光感受器快速变性。我们将利用这种突变体结合斑马鱼模型系统的优势来回答感光细胞生物学中的两个基本问题。1.什么是细胞类型和细胞密度的要求，导致死亡的健康光感受器在死亡的光感受器（“旁观者效应”）的存在？2.在缺乏磷酸二酯酶的情况下，导致视锥细胞退化的分子途径是什么？斑马鱼是一种脊椎动物模型系统，为研究视网膜变性提供了几个优势。在这种情况下，斑马鱼中PDE6c的缺失为收集有关视网膜变性的新信息提供了独特的机会。我们目前对感光细胞变性原因的理解不足以开发成功的治疗方法。斑马鱼发育迅速，视网膜特征明显。此外，它们是光学透明的，可以有效地用于遗传筛选，重要的是，可以通过细胞移植容易地进行镶嵌。这些特征将使我们能够超越在其他系统中开始的研究。来自斑马鱼模型的新信息将增强我们对视网膜变性的理解，并有助于开发治疗方法。我们计划利用我们对光感受器的光转导级联反应的详细了解以及斑马鱼特有的遗传和分子工具来确定刺激（目标#2）和预防（目标#3）变性的分子触发因素。我们还将使用我们的视锥变性突变体来制造含有突变体和非突变体视锥的混合物的镶嵌视网膜，以剖析引起旁观者效应所必需的参数（目标#1）。公共卫生相关性：斑马鱼是一种脊椎动物模型系统，为研究视网膜变性提供了几个优势。我们已经确定了一个盲目的突变斑马鱼与锥光感受器的快速退化，由于在锥磷酸二酯酶c基因（pde6c），锥光转导的关键调控组件的突变。斑马鱼突变体pde6cw59研究的新信息将增强我们对视网膜变性的理解，并有助于开发治疗这种常见遗传性失明的疗法。

DESCRIPTION (provided by applicant): We have identified a blind zebrafish mutant with rapid degeneration of cone photoreceptors due to a mutation in the cone phosphodiesterase c (pde6c) gene, a key regulatory component in cone phototransduction. We will use this mutant combined with the advantages of the zebrafish model system to answer two fundamental questions in photoreceptor biology. 1. What are the cell-type and cell density requirements that lead to the death of healthy photoreceptors in the presence of dying photoreceptors (the "bystander effect")? 2. What is the molecular pathway leading to cone degeneration in the absence of phosphodiesterase? Zebrafish is a vertebrate model system that provides several advantages for studying retinal degeneration. In this case, the loss of PDE6c in zebrafish provides a unique opportunity to gather new information about retinal degeneration. Our current understanding of the causes of photoreceptor degeneration is not sufficient to develop successful therapies. Zebrafish develop rapidly and have a well-characterized retina. Furthermore, they are optically clear, can be used efficiently in genetic screens and, importantly, can be made mosaic easily through cell transplantation. These features will enable us to go beyond studies begun in other systems. New information from the zebrafish model will enhance our understanding of retinal degeneration and aid in the development of therapies. We plan to take advantage of our detailed understanding of the photoreceptor's phototransduction cascade and the genetic and molecular tools unique to zebrafish to determine the molecular trigger(s) stimulating (Aim #2) and preventing (Aim #3) degeneration. We also will use our cone degeneration mutant to make mosaic retinas containing mixtures of mutant and non-mutant cones to dissect parameters essential for causing the bystander effect (Aim #1). PUBLIC HEALTH RELEVANCE: Zebrafish is a vertebrate model system that provides several advantages for studying retinal degeneration. We have identified a blind zebrafish mutant with rapid degeneration of cone photoreceptors due to a mutation in the cone phosphodiesterase c gene (pde6c), a key regulatory component in cone phototransduction. New information from the study of the zebrafish mutant pde6cw59 will enhance our understanding of retinal degeneration and aid in the development of therapies to treat this common inherited form of blindness.