Identification of genes regulating vertebrate intestinal development

鉴定调节脊椎动物肠道发育的基因

• 批准号: nhmrc : 280916
• 负责人: A/Pr Joan Heath
• 金额: $ 31.06万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/identification-genes-regulating-intestinal-development/82868
• 关键词: Identification; genes; regulating; vertebrate; intestinal

Colorectal cancer (CRC) causes 14 per cent of all cancer deaths in Australia. While early detection improves survival rate, nearly half of all CRC patients succumb to the disease within five years. In general, metastatic CRC is resistant to chemotherapy and radiotherapy and new therapies are required. An increased knowledge of the processes that contribute to the malignant state is likely to suggest new targets for treatment. CRC, like all cancer, is the result of genetic abnormalities (mutations) that are acquired over the course of a lifetime. Together the mutated genes produce changes in cell behaviour in processes such as growth, migration, angiogenesis (the ability to attract a blood supply) and cell death. All of these processes are active during normal development of a vertebrate organism, but are generally shutdown in the adult state, except in cancer. In this study, we propose to identify a set of genes that control the development of the intestine in a small tropical fish, the zebrafish. Zebrafish are vertebrate organisms, closely related to mice and man. Essentially all the pathways regulating development are conserved in the three species. The zebrafish offers several advantages: they are small, easy to breed, cheap to maintain and, most importantly, their embryos are transparent, making it possible to visualise development in live embryos in a simple microscope. Our project will use a panel of mutant strains of zebrafish that have an array of visible abnormalities in intestinal development. The abnormalities were induced using a chemical that produces single base pair changes in DNA. An established technique called positional cloning will allow us to identify the genes in which the mutations have been introduced, and provide a genetic explanation for the intestinal abnormalities. Upon identification of the mutated genes, our ultimate aim will be to test whether they also play a role in the development of CRC, using mouse models and human tissues.

在澳大利亚，结肠直肠癌（CRC）占所有癌症死亡人数的14%。虽然早期发现可以提高生存率，但近一半的CRC患者在五年内死于该疾病。一般来说，转移性CRC对化疗和放疗有抗性，需要新的治疗方法。对导致恶性状态的过程的更多了解可能会提出新的治疗目标。CRC与所有癌症一样，是一生中获得的遗传异常（突变）的结果。这些突变的基因一起在细胞生长、迁移、血管生成（吸引血液供应的能力）和细胞死亡等过程中产生细胞行为的变化。所有这些过程在脊椎动物生物体的正常发育期间都是活跃的，但在成年状态下通常会关闭，但癌症除外。在这项研究中，我们建议确定一组基因，控制肠道的发展，在一个小的热带鱼，斑马鱼。斑马鱼是一种脊椎动物，与人类和小鼠有着密切的亲缘关系，基本上所有的发育调控途径在这三个物种中都是保守的。斑马鱼有几个优点：它们体积小，易于繁殖，维护成本低，最重要的是，它们的胚胎是透明的，可以在简单的显微镜下观察活胚胎的发育。我们的项目将使用一组斑马鱼突变株，这些突变株在肠道发育中有一系列可见的异常。这些异常是使用一种化学物质诱导的，这种化学物质会在DNA中产生单碱基对的变化。一种被称为定位克隆的成熟技术将使我们能够识别引入突变的基因，并为肠道异常提供遗传学解释。在鉴定出突变基因后，我们的最终目标将是使用小鼠模型和人体组织来测试它们是否也在CRC的发展中发挥作用。