Development of a fish model for dyskeratosis congenita and cancer research

开发用于先天性角化不良和癌症研究的鱼类模型

• 批准号: 7512983
• 负责人: Julian J-L Chen
• 金额: $ 21.79万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7512983
• 关键词: Address; Aging; Anemia; Animal Model; Aplastic Anemia; Backcrossings; Biological; Biological Models; Biology; Biomedical Research; Blood Cells; Breeding; Cell division; Cells; Chromosomes; Defect; Development; Disease; Dyskeratosis Congenita; Enzymes; Exhibits; Fishes; Frequencies; Functional disorder; Generations; Genes; Genetic; Germ Cells; Germ Lines; Goals; Hamman-Rich syndrome; Hand; Hematopoiesis; Heterozygote; Human; Infertility; Kidney; Knock-out; Laboratory mice; Length; Libraries; Link; Malignant Neoplasms; Modeling; Mus; Mutation; Nonsense Mutation; Numbers; Pancytopenia; Phenotype; Play; Population; Premature aging syndrome; Public Health; Role; Role playing therapy; Screening procedure; Stem cells; Study models; Symptoms; Telomerase; Telomere Shortening; Vertebrates; Zebrafish; anticancer research; cancer stem cell; human disease; mutant; neoplastic cell; programs; size; teleost fish; telomerase reverse transcriptase; telomere; tumor; tumorigenesis; Address; Aging; Anemia; Animal Model; Aplastic Anemia; Backcrossings; Biological; Biological Models; Biology; Biomedical Research; Blood Cells; Breeding; Cell division; Cells; Chromosomes; Defect; Development; Disease; Dyskeratosis Congenita; Enzymes; Exhibits; Fishes; Frequencies; Functional disorder; Generations; Genes; Genetic; Germ Cells; Germ Lines; Goals; Hamman-Rich syndrome; Hand; Hematopoiesis; Heterozygote; Human; Infertility; Kidney; Knock-out; Laboratory mice; Length; Libraries; Link; Malignant Neoplasms; Modeling; Mus; Mutation; Nonsense Mutation; Numbers; Pancytopenia; Phenotype; Play; Population; Premature aging syndrome; Public Health; Role; Role playing therapy; Screening procedure; Stem cells; Study models; Symptoms; Telomerase; Telomere Shortening; Vertebrates; Zebrafish; anticancer research; cancer stem cell; human disease; mutant; neoplastic cell; programs; size; teleost fish; telomerase reverse transcriptase; telomere; tumor; tumorigenesis

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.

描述（由申请人提供）：端粒酶在细胞不朽中起着至关重要的作用，并且在大多数肿瘤细胞以及干细胞和生殖系中表达。几个端粒酶基因的突变，例如端粒酶逆转录酶（TERT）已与患有骨髓衰竭症状的人类疾病（如dkcc）（DKC）和性障碍性贫血（AA）遗传有关。端粒酶缺乏症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的。在过去的几十年中，斑马鱼和梅达卡鱼等硬鱼（例如斑马鱼和梅达卡鱼）已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，因为它们的大小和大量的后代。我们成功地产生了一种突变的Medaka鱼，其中包含Medaka tert基因中的无意义突变Tertk195x。这是有史以来第一个创建的端粒酶模型。该提议的计划的总体目标是开发和使用Medaka鱼类模型进行端粒和端粒酶研究，以及它们在DKC和肿瘤发生中的作用。该项目的第一个具体目的将集中于端粒长度表型和Tertk195x突变Medaka鱼的生殖细胞缺陷的表征。第二个特定目标将重点放在端粒酶缺乏症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至关重要的酶，在癌症，衰老和几种人类疾病中起关键作用，包括炎症性脑炎，性贫血和特发性肺纤维化。通过产生缺乏端粒酶的突变鱼类，我们将开发一种强大的鱼类模型系统，用于研究细胞中端粒酶和端粒的生物学作用，并为癌症和端粒酶功能疾病找到潜在的治疗方法。