Photoreceptor degeneration and rescue in zebrafish

斑马鱼光感受器变性与拯救

基本信息

批准号：
8288208
负责人：
Susan E Brockerhoff
金额：
$ 37.07万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-07-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：我们已经鉴定出一种盲斑马鱼突变体，该突变体由于视锥细胞磷酸二酯酶 c (pde6c) 基因（视锥光转导中的关键调节成分）的突变而导致视锥光感受器快速退化。我们将利用这种突变体结合斑马鱼模型系统的优点来回答光感受器生物学中的两个基本问题。 1. 在死亡光感受器存在的情况下，导致健康光感受器死亡的细胞类型和细胞密度要求是什么（“旁观者效应”）？ 2. 在没有磷酸二酯酶的情况下导致视锥细胞变性的分子途径是什么？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多种优势。在这种情况下，斑马鱼 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。我们目前对光感受器变性原因的了解不足以开发成功的治疗方法。斑马鱼发育迅速，并具有特征明确的视网膜。此外，它们是光学透明的，可以有效地用于遗传筛选，而且重要的是，可以通过细胞移植轻松制成镶嵌体。这些功能将使我们能够超越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。我们计划利用对光感受器光转导级联的详细了解以及斑马鱼独特的遗传和分子工具来确定刺激（目标#2）和预防（目标#3）退化的分子触发因素。我们还将使用我们的视锥细胞退化突变体来制作包含突变和非突变视锥细胞混合物的马赛克视网膜，以剖析引起旁观者效应所必需的参数（目标＃1）。公共健康相关性：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多种优势。我们发现了一种盲斑马鱼突变体，由于视锥磷酸二酯酶 c 基因（pde6c）（视锥光转导中的关键调节成分）发生突变，其视锥光感受器快速退化。来自斑马鱼突变体 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。