The platinum zebrafish is a model for studying vision defects caused by albinism

描述（由申请人提供）：白化病是一组遗传缺陷，发生在1/17，000出生，并导致眼睛，皮肤和头发色素沉着的损失。所有受影响的人都表现出视力问题，大多数人在法律上是盲人。然而，白化病个体中光感受器丧失的发病机制是复杂的，并且还没有被很好地理解。在许多情况下，关于色素沉着如何影响感光细胞活力的数据是矛盾的。斑马鱼铂突变体表现出色素沉着减少、视网膜色素上皮（RPE）变性和光感受器损失。我们确定铂斑马鱼在vps 11（空泡蛋白分选11）基因中含有突变，这与Hermansky-Pudlak综合征（HPS）有关，HPS是一种由蛋白质运输缺陷引起的白化病。因为目前还没有已知的小鼠，苍蝇，或蠕虫突变体在相应的vps 11基因，我们希望我们的分析铂视网膜病理学将有助于更广泛地了解空泡分选蛋白在HPS的作用和发病机制的光感受器损失的白化病个人。遗传和细胞技术将用于确定Vps 11在视网膜和RPE发育中的作用，并研究铂突变体如何发展其视网膜表型。具体而言，敲低和过表达实验将证实铂突变体表型由vps 11基因突变引起。接下来，将确定vps 11表达，并使用行为、超微结构、免疫组织化学和组织学方法评估眼部铂突变表型。最后，将确定铂突变体中RPE和感光体缺陷的细胞自主性。该建议将建立铂斑马鱼突变体作为一种新的模型，用于研究与HPS相关的视觉缺陷的机制，并确定视网膜色素上皮细胞在白化病个体感光细胞损失中的作用。这项研究的意义在于：1）探索铂突变体中Vps 11蛋白丢失的后果; 2）阐明导致一类白化病患者视力丧失的细胞和分子事件。这项工作可能最终揭示新的目标，为发展的疗法，以防止视力丧失的人患有白化病。 公共卫生相关性：所有受白化病影响的人都表现出视力问题，大多数人在法律上是盲人。然而，白化病感光细胞损失的发病机制是复杂的，知之甚少。我们的目标是建立铂斑马鱼突变体作为模型，研究与白化病相关的视觉缺陷的机制。

DESCRIPTION (provided by applicant): Albinism is group of genetically inherited defects that occurs in 1 in 17,000 births and results in loss of pigmentation in the eyes, skin, and hair. All affected individuals exhibit vision problems and most are legally blind. However, the pathogenesis of photoreceptor loss in albino individuals is complex and is not well understood. In many cases, the data are contradictory in regard to how pigmentation affects photoreceptor viability. The zebrafish platinum mutant exhibits reduced pigmentation, degeneration of the retinal pigmented epithelium (RPE), and photoreceptor loss. We determined that platinum zebrafish contain a mutation in the vps11 (vacuolar protein sorting 11) gene, which is associated with Hermansky-Pudlak syndrome (HPS), a defined class of albinism that results from defective protein trafficking. Because there are currently no known mouse, fly, or worm mutants in the corresponding vps11 gene, we expect that our analysis of the platinum retinal pathology will contribute to broader understanding of the role of the vacuolar sorting proteins in HPS and the pathogenesis of photoreceptor loss in albino individuals. Genetic and cellular techniques will be used to determine the role of Vps11 in retinal and RPE development and examine how the platinum mutant develops its retinal phenotype. Specifically, knock-down and overexpression experiments will confirm that the platinum mutant phenotypes result from a mutation in the vps11 gene. Next, vps11 expression will be determined and the ocular platinum mutant phenotype will be assessed using behavioral, ultrastructural, immunohistochemical, and histological methods. Finally, the cell autonomy of the RPE and photoreceptor defects in the platinum mutant will be determined. This proposal will establish the platinum zebrafish mutant as a novel model for studying the mechanisms underlying vision defects associated with HPS and determine the role of the retinal pigmented epithelium in photoreceptor loss in albino individuals. The significance of the proposed research is to: 1) explore the consequences of Vps11 protein loss in the platinum mutant and 2) elucidate the cellular and molecular events leading to vision loss in one class of albinism. This work could ultimately reveal new targets for the development of therapies to prevent vision loss in persons afflicted with albinism. PUBLIC HEALTH RELEVANCE: All individuals affected with albinism exhibit vision problems and most are legally blind. However, the pathogenesis underlying photoreceptor loss in albinism is complex and poorly understood. We aim to establish the platinum zebrafish mutant as a model for studying the mechanisms underlying vision defects associated with albinism.