Photoreceptor degeneration and rescue in zebrafish

描述(申请人提供)：我们已经鉴定出一个盲斑马鱼突变体，由于锥体磷酸二酯酶c(Pde6c)基因的突变，导致锥体光感受器迅速退化，该基因是锥体光转导的关键调节成分。我们将利用这个突变体结合斑马鱼模型系统的优势来回答感光生物学中的两个基本问题。1.什么细胞类型和细胞密度要求导致健康的光感受器在死亡的感光细胞存在下死亡(“旁观者效应”)？2.在没有磷酸二酯酶的情况下导致视锥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许多优势。在这种情况下，斑马鱼中PDE6c的缺失为收集有关视网膜退化的新信息提供了一个独特的机会。我们目前对光感受器退化原因的了解不足以开发成功的治疗方法。斑马鱼发育迅速，具有良好的视网膜特征。此外，它们在光学上是透明的，可以有效地用于基因筛选，更重要的是，可以通过细胞移植轻松地进行镶嵌。这些特点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退化的理解，并有助于治疗方法的开发。我们计划利用我们对光感受器的光转导级联以及斑马鱼特有的遗传和分子工具的详细了解来确定分子触发因素(S)刺激(目标2)和防止(目标3)退化。我们还将使用我们的视锥退化突变体来制作包含突变视锥和非突变视锥混合的马赛克视网膜，以剖析导致旁观者效应的关键参数(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。我们已经发现了一个盲斑马鱼突变体，由于锥体磷酸二酯酶c基因(Pde6c)的突变导致了锥体光感受器的快速退化，pde6c是锥体光转导的关键调节成分。对斑马鱼突变体pde6cw59的研究提供的新信息将增强我们对视网膜退化的理解，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.