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 / 17000新生儿中，导致眼睛，皮肤和头发色素沉着丧失。所有受影响的人都表现出视力问题，大多数人在法律上都是盲人。然而，白化病患者光感受器丧失的发病机制是复杂的，并没有很好地理解。在许多情况下，关于色素沉着如何影响光感受器活力的数据是矛盾的。斑马鱼铂突变体表现为色素沉着减少，视网膜色素上皮（RPE）变性和光感受器丧失。我们确定铂斑马鱼含有vps11（液泡蛋白分选11）基因突变，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。由于目前还没有已知的小鼠、苍蝇或蠕虫对应的vps11基因突变体，我们希望我们对铂视网膜病理的分析将有助于更广泛地了解空泡分选蛋白在HPS中的作用以及白化病个体光感受器丧失的发病机制。遗传和细胞技术将用于确定Vps11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。具体来说，敲除和过表达实验将证实铂突变表型是由vps11基因突变引起的。接下来，将测定vps11的表达，并使用行为学、超微结构、免疫组织化学和组织学方法评估眼铂突变表型。最后，确定铂突变体中RPE和光感受器缺陷的细胞自主性。本研究将建立白斑马鱼突变体作为研究HPS相关视力缺陷机制的新模型，并确定视网膜色素上皮在白化个体光感受器丧失中的作用。本研究的意义在于：1)探索铂突变体中Vps11蛋白丢失的后果；2)阐明一类白化病中导致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，为开发治疗方法，以防止白化病患者的视力丧失。

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.