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上进行发育和生殖毒性(DART)测试，以评估化学物质对人类健康的风险。迫切需要改进用于使用替代测试评估DART终端的流程。这一需求已经得到了DART研究界、监管机构以及制药和农化行业的认可。最近，有人提议使用所谓的“新方法方法论”(NAMS)进行替代评估。包括斑马鱼在内的NAMS有可能显著减少制药行业在DART评估中使用的哺乳动物数量，并支持测试中替换、减少、改进(3Rs)的原则。学生将加入埃克塞特充满活力的大型生物科学研究团队，接受尖端分子技术、生物信息学、活体研究、先进成像技术和病理学方面的培训，应用于开发非哺乳动物替代模型和在动物应用中推动NC3Rs原则。该项目将与我们的行业合作伙伴阿斯利康(在英国和瑞典)合作，包括使用一种新的基因编辑技术(CRISPR/Cas9)来生成新的斑马鱼模型，用于评估药物的致畸作用。学生还将与NC3R合作，并与更广泛的学者和利益相关者接触，帮助说明斑马鱼在非保护生命阶段(高达4dpf)的效用，以检测已知可在人/兔身上引起致畸效应的选定免疫调节性亚胺药物(例如，沙利度胺、来那度胺和泊马度胺)的发育影响。

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).