Building confidence in non-protected zebrafish embryo-larvae as a viable alternative to mammalian DART assessment. (Ref 4649)

在啮齿动物和兔子模型中进行发育和生殖毒性（DART）测试，以评估化学品对人类健康的风险。迫切需要改进使用替代测试评估DART终点的过程。这一需求已经得到了DART研究界、监管机构、制药和农用化学品行业的认可。最近，有人提出使用所谓的“新方法"进行替代评估。NAM，其中包括斑马鱼，有可能显着减少哺乳动物的数量用于DART评估制药行业和支持的原则，取代，减少，完善（3R）在测试中。学生将加入一个大型的充满活力的研究团队在生物科学在埃克塞特和接受培训，在尖端的分子技术，生物信息学，在生活中的研究，先进的成像技术和病理学，应用于开发非哺乳动物替代模型和推动动物使用NC 3Rs原则。与我们的行业合作伙伴阿斯利康（英国和瑞典）合作，该项目将包括使用一种新的基因编辑技术（CRISPR/Cas9）来生成一种新的斑马鱼模型，用于评估药物的致畸作用。学生还将与NC 3R合作，并更广泛地与学者和利益相关者接触，以帮助说明斑马鱼在非保护生命阶段（高达4dpf）的效用，用于检测已知在人类/兔子中诱导致畸作用的选定免疫调节酰亚胺药物的发育影响（例如，沙利度胺、来那度胺和泊马度胺）。

Developmental and Reproductive Toxicity (DART) tests are conducted in rodent and rabbit models in order to assess for chemical risk to human health. There is an urgent need to refine the processes used to assess DART endpoints using alternative tests. This need has been recognised by the DART research community, regulators, and pharmaceutical and agrochemical industries. Recently the use of so called 'New Approach Methodologies' (NAMs) for alternative assessments have been proposed. NAMs, which include the zebrafish, have the potential to significantly reduce the numbers of mammals used in DART assessment by the pharmaceutical industry and supporting the principle of replace, reduce, refine (3Rs) in testing.The student will join a large vibrant research team in Biosciences at Exeter and recieve training in cutting edge molecular technologies, bioinformatics, in-life studies, advanced imaging techniques and pathology, as applied to developing non-mammalian alternative models and driving the NC3Rs principles in animal use. Working in collaboration and alongside our industry partner, AstraZeneca (both in the UK and Sweden) the project will include use a novel gene editing technology (CRISPR/Cas9) to generate a new zebrafish model for assessing teratogenic effects of pharmaceuticals. The student will work also with NC3Rs, and engage with academics and stakeholders more widely to help illustrate the utility of zebrafish in non-protected life stages (up to 4dpf) for detecting developmental effects of selected ImmunoModulatory imide drugs known to induce teratogenic effects in humans/rabbits (e.g., thalidomide, lenalidomide and pomalidomide).