The Zebrafish Model of Microphthalmia

斑马鱼小眼症模型

• 批准号: 7925054
• 负责人: JAREMA MALICKI
• 金额: $ 7.43万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925054
• 关键词: Affect; Animal Model; Animals; Anophthalmos; Candidate Disease Gene; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Child; Class; Collaborations; DNA; Defect; Development; Disease; Embryonic Development; Expression Feature; Eye; Eye Neoplasms; Eye diseases; Genes; Genetic; Genetic Screening; Goals; Growth; Growth Disorders; Human; Individual; Knowledge; Lead; Length; Malignant Neoplasms; Maps; Medical; Microphthalmos; Modeling; Molecular; Mutation; Nature; Normal tissue morphology; Nucleic Acids; Numbers; Organism; Pattern; Phenotype; Process; Regulation; Research; Retinal; Running; Sampling; Source; Testing; Time; Vertebrates; Vision; Zebrafish; base; insight; mutant; neurogenesis; retinal progenitor cell; size; success; zebrafish genome

DESCRIPTION (provided by applicant): The regulation of tissue growth is of paramount importance for the understanding of vertebrate, including human, embryogenesis. It has also a tremendous medical significance. Deviations from normal tissue growth lead to severe patterning defects during embryogenesis, and to cancer in the mature organism. Abnormal patterns of cell proliferation produce a number of developmental eye disorders in humans. One of them is microphthalmia, which in the most extreme cases leads to the complete absence of eyes. To identify the genetic causes of human microphthalmia and anophthalmia, we chose to use an animal model, the zebrafish. Genetic screens in zebrafish identified many mutations that result in a decreased eye size. One of the most severe small eye phenotypes is caused by defects of the out of sight (out) locus. The goal of this project is to identify the molecular nature of the out gene, and to develop an understanding of its function on the cellular level. Once the molecular identity of this gene is known, we will investigate whether its defects are responsible for human microophthalmia by screeing DNA samples from diseased individuals. Similar animal model-based approaches have been very productive, leading to the identification of microphthalmia-causing mutations in several genes, including rx, six6, and sox2. This project is the first step on the way to use zebrafish mutants on a broader scale to identify the genetic causes of eye growth disorders. In the long run, the zebrafish is likely to become a major source of candidate genes to study this class of abnormalities. This strategy is likely to make a major contribution to the understanding of the genetic causes of microphthalmia and its more severe form, anophthalmia, in humans. We will use animal model, the zebrafish, to identify genes responsible for microphthalmia, a human eye disorder characterized by a reduction of eye size, and in the most extreme the absence of eyes. These studies will provide insight into the genetic basis of this debilitating disorder that affects 1 in 5,000 children.

描述（由申请人提供）：组织生长的调节对于理解脊椎动物（包括人类的胚胎发生）至关重要。它也具有巨大的医学意义。正常组织生长的偏差会导致胚胎发生过程中严重的模式缺陷，并导致成熟生物体的癌症。细胞增殖的异常模式在人类中产生许多发育性眼部疾病。其中之一是微观心脏，在最极端的情况下，这完全导致完全没有眼睛。为了鉴定人类微观心脏病和性疾病的遗传原因，我们选择使用动物模型，即斑马鱼。斑马鱼中的遗传筛选确定了许多突变，导致眼睛尺寸降低。最严重的小眼表型之一是由于视线（外部）的缺陷引起的。该项目的目的是确定OUT基因的分子性质，并在细胞水平上发展其功能。一旦已知该基因的分子身份，我们将通过从患病个体的DNA样本中调查其缺陷是否负责人类微感。类似的基于动物模型的方法非常有生产力，导致在包括RX，SIX6和SOX2在内的几个基因中鉴定出微粒疫血的突变。该项目是在更广泛的规模上使用斑马鱼突变体的第一步，以确定眼睛生长障碍的遗传原因。从长远来看，斑马鱼可能会成为研究此类异常的主要基因的主要来源。该策略可能会为理解微观粒细胞的遗传原因及其更严重的形式，消性心脏病做出重大贡献。我们将使用动物模型，斑马鱼来识别导致微观噬菌体的基因，这是一种以减小眼睛大小的人为特征的人眼疾病，并且最极端的是没有眼睛。这些研究将洞悉影响5,000名儿童中1个衰弱障碍的遗传基础。

项目成果

Genetic defects of GDF6 in the zebrafish out of sight mutant and in human eye developmental anomalies.

• DOI: 10.1186/1471-2156-11-102
• 发表时间: 2010-11-11
• 期刊: BMC genetics
• 影响因子: 2.9
• 作者: den Hollander AI;Biyanwila J;Kovach P;Bardakjian T;Traboulsi EI;Ragge NK;Schneider A;Malicki J
• 通讯作者: Malicki J