Photoreceptor degeneration and rescue in zebrafish

描述（由申请人提供）：我们已经发现了一种失明斑马鱼，由于锥体磷酸二酯酶c （pde6c）基因突变，导致锥体光感受器快速退化，pde6c基因是锥体光传导的关键调控成分。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光感受器生物学中的两个基本问题。1. 在死亡的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. 在缺乏磷酸二酯酶的情况下，导致锥体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许多优势。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一个独特的机会。我们目前对光感受器变性的原因的了解还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，它们在光学上是透明的，可以有效地用于基因筛选，重要的是，可以通过细胞移植很容易地进行镶嵌。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，并有助于治疗方法的发展。我们计划利用我们对光感受器光传导级联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（Aim #2）和预防（Aim #3）退化的分子触发器。我们还将使用我们的锥体变性突变体来制作包含突变体和非突变体锥体混合物的马赛克视网膜，以解剖引起旁观者效应的必要参数（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。我们已经发现了一种失明斑马鱼，由于锥体磷酸二酯酶c基因（pde6c）的突变，导致锥体光感受器快速退化，pde6c基因是锥体光传导的关键调控成分。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。

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.