Thalidomide was discovered to be teratogenic over 50 years ago, but is far from being a historical problem. A new generation of thalidomide survivors have been reported in Brazil, where the drug is used to treat leprosy complications and multiple myeloma. The mechanisms underlying thalidomide teratogenesis are not fully understood. Cereblon (CRBN) protein has been identified as a target of thalidomide. Cereblon is part of an E3 ubiquitin ligase complex with Damaged DNA Binding protein 1 and Cullin-4A. I have analysed the expression patterns of CRBN and its binding partners in wildtype and thalidomide-treated chicken and zebrafish embryos. My results show that CRBN complex genes are weakly expressed in multiple tissues, including those not affected by thalidomide, and do not change following thalidomide exposure. I have also investigated the teratogenic potential of Primodos, a drug claimed to be “the forgotten thalidomide”. This drug was used as a pregnancy test between 1950's and 1970's. Primodos is alleged to be teratogenic but still is not recognised as one. Several epidemiological studies have been conducted, with conflicting results. I have been analysing the teratogenic properties of Primodos in chicken and zebrafish embryos and found that Primodos causes a range of malformations in zebrafish embryos. I have also carried out molecular analyses that show Primodos causes gene expression changes, changes in blood vessel patterning and neurite outgrowth in vivo and in vitro and increase in cell death. Finally, I have investigated the role of blood vessels in limb development and patterning. Using an antiangiogenic analogue of thalidomide, I found that inducing blood vessel loss in different regions of the forelimb bud of developing chicken results in different phenotypes. My results suggest that blood vessels might be involved in limb patterning and progress the understanding of limb defects observed in thalidomide survivors.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:701784 |
| Date | January 2016 |
| Creators | Rosa Fraga, Lucas |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=231144 |
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