The Drosophila adult intestine as a model for radiation tolerance and resistance

果蝇成年肠道作为辐射耐受性和抵抗力的模型

• 批准号: NC/M000710/1
• 负责人: Joaquin De Navascués
• 金额: $ 9.46万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FM000710%2F1
• 关键词: Drosophila; adult; intestine; model; radiation

Radiation therapy is an essential tool in the treatment of cancer. It is very cost effective, and responsible for 40% of cures, with chemotherapy contributing to 11% and surgery to 49% of cures. The reason why this treatment works is that radiation is toxic for all cells, but tumour cells are generally more sensitive to radiation. (Broadly speaking, the same principle applies to chemotherapy.) Treatment is applied with the aim of killing the tumour before causing too much damage in the healthy tissue of the patient. Therefore, radiotherapy can have serious side effects both shortly after treatment and in the longer term. Moreover, some tumours turn out to be very resistant to radiotherapy. The combination of this tumour resistance and the toxicity for the patient is an important limitation to the successful application of radiotherapy.To overcome this limitation, we need to understand what are the causes of resistance in the tumours and of sensitivity in the healthy tissue. For instance, we know that tumours that switch on certain genes are protected from radiation; one could design a drug that prevents one of these genes from functioning and so improve the sensitivity of that type of tumours to radiotherapy. On the other hand, we need to understand how radiation causes malfunctioning in the healthy tissue. For instance, we know that specific cell types are particularly sensitive to radiation; identifying the factors that make them sensitive could help to design preventive or corrective treatments for the side effects of radiotherapy.Research in this area is very active and has been identified as a priority for the UK by the National Cancer Research Institute. This type of research is conducted to some extent using cells in culture dishes. However, before any progress in medical practice takes place, research in whole animals (mostly mice and rats) is necessary, as it is not always the case that observations made with cultured cells are relevant to what happens in real tissues. With the aim of replacing the use of mice and rats, we want to establish the fruit fly as an alternative species where to study radiation sensitivity in whole animals.Fruit flies are used for research in many areas of biology, as they are cheap and there are many experimental tools available to work with them. Moreover, the genes that provide resistance to radiotherapy in tumours have an equivalent in flies, and therefore knowledge obtained in flies about the functioning of these genes could have applicability in humans. We will focus on the fly intestine because many cancer patients have long-term intestinal side effects due to radiotherapy.To test whether the fly intestine can be a useful research system to improve radiotherapy in substitution of rodents, we will seek to establish:(1) whether the side effects of radiotherapy in humans are also mirrored in the fly intestine,(2) whether we can identify genes and drugs that improve the tolerance of the healthy tissue, and(3) whether we can create tumour-like cells inside the fly intestine that show increased radio resistance when they switch on the tumour radio resistance genes.If we establish these observations successfully, this will indicate that the fly intestine can be used effectively in radiotherapy research in substitution of mice and rats, and we will advertise our findings to scientists working in this field, to encourage such replacement.

放射治疗是治疗癌症的一种重要手段。它非常具有成本效益，占治愈率的40%，化疗占11%，手术占49%。这种治疗有效的原因是辐射对所有细胞都是有毒的，但肿瘤细胞通常对辐射更敏感。（一般来说，同样的原则也适用于化疗。治疗的目的是在对患者的健康组织造成太大损害之前杀死肿瘤。因此，放射治疗在治疗后不久和长期内都可能产生严重的副作用。此外，一些肿瘤对放射治疗非常有抵抗力。这种肿瘤抵抗力和对患者的毒性是成功应用放射治疗的一个重要限制因素。为了克服这一限制，我们需要了解肿瘤抵抗力和健康组织敏感性的原因。例如，我们知道开启某些基因的肿瘤可以免受辐射的影响;人们可以设计一种药物，阻止这些基因中的一种发挥作用，从而提高这种类型的肿瘤对放射治疗的敏感性。另一方面，我们需要了解辐射如何导致健康组织发生故障。例如，我们知道特定的细胞类型对辐射特别敏感;确定使它们敏感的因素有助于设计预防或纠正放射治疗副作用的治疗方法。这方面的研究非常活跃，已被国家癌症研究所确定为英国的优先事项。这种类型的研究在某种程度上是使用培养皿中的细胞进行的。然而，在医学实践取得任何进展之前，对整个动物（主要是小鼠和大鼠）的研究是必要的，因为对培养细胞的观察并不总是与真实的组织中发生的情况相关。为了取代小鼠和大鼠的使用，我们希望将果蝇作为研究整个动物辐射敏感性的替代物种。果蝇被用于生物学许多领域的研究，因为它们价格便宜，并且有许多实验工具可供使用。此外，在肿瘤中提供对放射治疗抗性的基因在苍蝇中具有等同物，因此在苍蝇中获得的关于这些基因功能的知识可能适用于人类。我们将重点放在苍蝇肠，因为许多癌症患者因放射治疗而产生长期的肠道副作用。为了测试苍蝇肠是否可以作为一个有用的研究系统来改善放射治疗，以替代啮齿动物，我们将寻求建立：（1）人类放射治疗的副作用是否也反映在苍蝇的肠道中，（2）我们是否可以识别提高健康组织耐受性的基因和药物，以及（3）我们是否可以在苍蝇肠道内创造出肿瘤样细胞，当它们打开肿瘤放射抗性基因时，它们显示出增加的放射抗性。如果我们成功地建立了这些观察结果，这将表明苍蝇肠可以有效地用于放射治疗研究，以取代小鼠和大鼠，我们将向这一领域的科学家宣传我们的发现，以鼓励这种替代。