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Wellcome Trust PhD Student Cohort 2017

Fay_TheaAcademic and Work Experience Prior to Sept 2017 Programme Start: I completed my undergraduate studies at the University of York, graduating with a BSc Biochemistry degree. During my bachelor's degree, I gained research experience by participating in the iGEM (International Genetically Engineered Machine) competition as a member of the team representing my university. I spent the third year of my four-year degree on an industrial placement at the Earlham Institute, improving my knowledge of bioinformatics and learning more about gene expression analysis and tissue culture.

PhD Programme – Year 1 – MRes and Project Rotations: In my first year of the Wellcome Trust ‘Cell Therapies and Regenerative Medicine’ Four-Year PhD Programme, I explored diverse aspects of the field of stem cells and regenerative medicine through my three rotation projects. I undertook my first rotation under the supervision of Professor Graham Lord and Dr Joana Neves, investigating plasticity triggers between different types of innate lymphoid cells within a 3D intestinal organoid co-culture system. During my second rotation, in Dr Eileen Gentleman’s group, I worked to characterise the effects of PEG hydrogels with different mechanical properties on iPSC differentiation towards the three germ layers, focusing in particular on the role of hydrogel stiffness, adhesiveness and degradability. Throughout my third rotation, carried out in Dr Rocio Sancho’s lab, I aimed to elucidate the role of Fbw7, an E3 Ubiquitin Ligase, in the proteasomal degradation of proendocrine transcription factors Pdx1 and MafA. As these transcription factors, alongside Ngn3, are essential in β-cell development, it is hoped that by identifying ubiquitin ligases involved in their degradation and impairing their function, we can enhance β-cell generation.

Fay_Thea cells 2018

PhD Programme – Years 2 to 4 – Doctoral Studies: In Type 1 Diabetes, insulin-producing β-cells in the pancreas are destroyed due to an autoimmune reaction, resulting in impaired insulin production and dysregulated glucose metabolism. Transplantation of pancreatic islets from healthy donors has been attempted, aiming to compensate for lost β-cells in diabetic patients, but a shortage of islets available for transplantation and the fact that the transplant must be accompanied by immunosuppression currently limits the clinical applications of this therapy. To circumvent these issues and boost β-cell generation, attempts have been made to identify triggers that could induce the ex vivo transition from the abundant exocrine pancreatic cells to β-cells. While inducing overexpression of β-cell development factors Pdx1, Ngn3 and MafA in exocrine cells through adenoviral infection was found to transdifferentiate them into β-like cells, this strategy does not result in fully functional β-cells, partly due to the incorrect regulation of the three transcription factors. My project, carried out within Dr Rocio Sancho’s lab, will investigate ways to stabilise Pdx1, Ngn3 and MafA levels post-translationally, focusing on the role of ubiquitin ligases Fbw7 and Huwe1. As preliminary data from the lab suggests that these ubiquitin ligases play a role in the degradation of at least some of the transcription factors of interest, we hypothesise that impairing their function could lead to stabilisation of Pdx1, Ngn3 and MafA, thus enhancing  β-cell generation.

Teodora Manea ORCID webpage

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