Development of a fish model for dyskeratosis congenita and cancer research

描述（由申请人提供）：端粒酶在细胞永生中起关键作用，并在大多数肿瘤细胞以及干细胞和生殖细胞系中表达。几种端粒酶基因（例如端粒酶逆转录酶（TERT））中的突变已经在遗传上与具有骨髓衰竭症状的人类疾病（例如先天性角化不良（DKC）和再生障碍性贫血（AA））相关。端粒酶缺乏的生物学后果主要是使用培养的人类细胞或小鼠作为动物模型进行研究。硬骨鱼，如斑马鱼和青鳉鱼，在过去的几十年里已经成为强大的遗传模型系统。它们是生物医学研究的有吸引力的脊椎动物模型，因为它们的体积小，每代有大量的后代。我们已经成功地产生了一个突变青鳉鱼，其中包含一个无义突变TERTK195X青鳉TERT基因。这是有史以来第一个缺乏端粒酶的鱼类模型。该计划的总体目标是开发和使用青鳉鱼模型来研究端粒和端粒酶及其在DKC和肿瘤发生中的作用。该项目的第一个具体目标将集中在TERTK195X突变青鳉鱼的端粒长度表型和生殖细胞缺陷的表征。第二个具体目标将集中在端粒酶缺陷和端粒功能障碍在造血和肿瘤发生中的作用。公共卫生相关性：端粒酶是细胞永生的关键酶，在癌症、衰老和包括先天性角化不良、再生障碍性贫血和特发性肺纤维化在内的几种人类疾病中起关键作用。通过产生缺乏端粒酶的突变鱼，我们将开发一个强大的鱼模型系统，用于研究细胞中端粒酶和端粒的生物学作用，并找到癌症和端粒酶功能障碍疾病的潜在治疗方法。

DESCRIPTION (provided by applicant): Telomerase plays a crucial role in cellular immortality and is expressed in most tumor cells as well as stem cells and germ lines. Mutations in several telomerase genes, e.g. telomerase reverse transcriptase (TERT), have been genetically linked to human diseases such as dyskeratosis congenita (DKC) and aplastic anemia (AA) that have symptoms of bone marrow failure. The biological consequences of telomerase deficiency have been studied mostly using cultured human cells or mice as an animal model. Teleost fish, such as zebrafish and medaka fish, have emerged as powerful genetic model systems in the past few decades. They are attractive vertebrate models for biomedical research because of their small size and large numbers of progeny per generation. We have successfully generated a mutant medaka fish that contains a nonsense mutation TERTK195X in the medaka TERT gene. This is the first telomerase-deficient fish model ever created. The overall goal of this proposed program is to develop and use the medaka fish model for the study of telomeres and telomerase, and their role in DKC and tumorigenesis. The first specific aim of this project will focus on characterization of telomere length phenotype and germ cell defect of the TERTK195X mutant medaka fish. The second specific aim will focus on the role of telomerase deficiency and telomere dysfunction in hematopoiesis and tumorigenesis. PUBLIC HEALTH RELEVANCE: Telomerase is an enzyme crucial for cellular immortality and play critical roles in cancer, aging and several human diseases including dyskeratosis congenita, aplastic anemia and idiopathic pulmonary fibrosis. By generating a mutant fish that lacks telomerase enzyme, we will develop a powerful fish model system for studying the biological roles of telomerase and telomeres in cells, and finding potential cures for cancer and telomerase-dysfunction diseases.