Evaluation of Organoids and Systems Biology to develop Adverse Outcome Pathways of Gastrointestinal Toxicity

Gastrointestinal (GI) toxicity remains a leading cause of drug attrition for Pharmaceuticals and is ranked 5th amongst causes of safety attrition in GSK. Unlike other areas of toxicity there are no robust in vitro assays or translational biomarkers that predict GI toxicity in animals or patients. Legacy GSK research contains a wealth of information regarding organ level, adverse non-clinical and clinical effects that can help define drug safety concerns. Adverse Outcome Pathways (AOP) provide a means to capture and organise information related to the causes of GI toxicity and identify gaps in knowledge. Identifying Molecular Initiating Events (MIE) for specific GI organ toxicities, supported by data from tissue specific organoids that reflects the complex cell architecture and interplay seen in vivo, will help characterise pathways that underpin a systems biology approach relevant to human risk assessment.

The aim of this 4 year PhD is to explore this hypothesis and harness the power of key platforms (complex in vitro GI organoids, hepatic organoids, transcriptomics & proteomics) with a focus on chemotheraputic drugs with known translational GI toxicity: (a) Irinotecan, a cytotoxic topoisomerase 1 inhibitor used to treat colon cancer; and its active metabolite SN38; (b) two GSK compounds, an endothelin receptor antagonist and a MEK inhibitor, where GI toxicity contributed to the termination of their development. Importantly, for all compounds, there is existing non-clinical safety/disposition data in animals (eg repeat dose toxicity, histopathology and DMPK) and data from the Clinic which can support Integrative Toxicology and anchor the systems biology approach in terms of translation.
The PhD project, training and supervision will be based at the University of Liverpool, under the supervision of Goldring (MRC Centre for Drug Safety Science) and Duckworth/Pritchard (Department of Cellular and Molecular Physiology) and, periodically, at GSK R&D Ware (Dept Mechanistic Safety & Disposition) under Allen/Lynch.

Qualifications and Experience
You should have, or expect to hold a first or upper second class honours degree in a relevant biological or medical sciences subject

*Please note the English Language Requirement for EU Students is an IELTS score of 6.5 with no band score lower than 5.5.

To apply please send CV (with two referees) and cover letter explaining why you would like the PhD studentship to [Email Address Removed].

For application enquires please contact Prof Chris Goldring ([Email Address Removed]) or Dr Carrie Duckworth ([Email Address Removed])