Phd Research Project- Metabolomic strategies to discover drug induced perturbations in cardiac mode
This exciting 4-year BBSRC iCASE PhD opportunity bridges the University of Birmingham’s (*) metabolomics team and AstraZeneca’s Drug Safety and Metabolism team, both having state-of-the-art facilities and renowned research programmes, thereby creating a challenging yet impactful research project.
* Winner of ‘University of the Year for Graduate Employment’, The Times and The Sunday Times Good University Guide 2015-16; 91% of our postgraduate researchers from the School of Biosciences were in work and/or further study six months after graduation.
Drug induced cardiovascular toxicity affects all components and functions of the cardiovascular system and can be functional (acute alteration of the mechanical function of the myocardium) and or structural in nature (morphological damage to cardiomyocytes and/or loss of viability). Evaluation of the potential for either functional or structural cardiotoxicity by novel compounds is essential for the discovery of safe drugs. Hence, discovering the molecular mechanisms that lead to these toxicities – including prognostic biomarkers – represents an urgent research activity with strong translational application.
A 21st century approach to studying metabolic biochemistry – termed metabolomics – offers the opportunity for discovering normal and perturbed metabolic mechanisms in cardiac cell biology. Metabolomics represents an integration of metabolic biochemistry, bioanalytical chemistry and bioinformatics and is exceptionally powerful at discovering novel molecular mechanisms, benefiting from non-targeted measurements of many hundreds to thousands of metabolites (such as energy metabolism, amino acid metabolism and lipid biochemistry). Previously, metabolic alterations have been linked to various cardiovascular disease phenotypes including heart failure and myocardial infarction (Dunn et al. 2011; Kordalewska and Markuzewski 2015).
To achieve this vision, advanced model systems with greater complexity and thus physiological relevance than traditional in vitro cell culture, e.g. microtissues and microphysiological systems (MPS) such as organs-on-chips or 3D organ constructs that use human cells, need to be applied to the metabolomics field in conjunction with biofluids/tissues from preclinical species and clinical samples. However, this presents challenges in terms of the analytical tools, due to the small sample masses. We therefore also need to adapt contemporary metabolomics technologies to enable their application to cutting edge advanced cardiac in vitro models including cardiac microtissues.
1. Implement and optimise an analytical metabolomics workflow for low biomass cardiac tri-culture microtissues (cardiomyocytes, cardiac fibroblasts and cardiac endothelial cells), including sample pre-treatment and high sensitivity LC-MS, to facilitate reproducible measurements of their metabolic fingerprints.
2. Characterise metabolic fingerprints in cardiac microtissues (and potentially an MPS model) following phenotypic perturbations of cardiac cell biology (via selected drugs). Additional omics data will be collected and integrated with the metabolomics measurements to discover the underlying molecular mechanisms, and prognostic biomarkers, in response to cardiotoxicants.
3. To facilitate translation of the knowledge generated above, derived from the multi-omics measurements, complementary fingerprints using the same tools to modulate cell biology will be obtained in the rat and if available clinical samples.
4. Based on the integrated findings, further empirical evidence will be established to determine the role of the pathways / proteins identified via siRNA. This will likely include knockdown of key proteins, reporter assays and assessment of phenotypic cardiac responses in vitro on cell health and function.
5. Ultimately, the knowledge discovered during the PhD will be used to build quantitative relationships between the observations, contributing towards the longer term aim to develop an in vitro to in vivo systems pharmacology model of cardiac cell biology perturbations.
Advanced analytical techniques to be employed include small biomass metabolic extractions and clean-up, capillary LC-MS metabolomics, transcriptomics, bioinformatics and statistics, culturing of complex organotypic cell models, measurement of calcium transients, live cell imaging of key organelles, immunofluorescence, siRNA, and reporter assays, with the student training at both the University of Birmingham and AstraZeneca (Cambridge). The metabolomics team comprises of ca. 25 PhD students and postdoctoral researchers. The School of Biosciences was ranked in 6th in the UK Russell Group in REF2014, with >90% of research rated as world leading.
Are you right for this Phd?
We seek an excellent, highly motivated candidate with a high quality undergraduate and/or Masters degree (can be pending) in fields such as pharmacology, toxicology, biochemistry or bioanalytical chemistry.
This BBSRC studentship is for 4 years. In addition to the payment of tuition fees, the award provides an annual stipend and funds for the laboratory studies. AstraZeneca are providing further funding for this PhD, as is the University of Birmingham. Note that this PhD funding is for UK HOME STUDENTS ONLY, meaning it is open to UK citizens, or to EU citizens who have lived in the UK for the last three years.
Cross et al., 2015, Br J Pharmacol 172, 957-974. Physiological, pharmacological and toxicological considerations of drug-induced structural cardiac injury.
Dunn, Goodacre, Neyses, Mamas, 2011, Bioanalysis 3, 2205-22. Integration of metabolomics in heart disease and diabetes research: current achievements and future outlook.
Dunn et al., 2011, Nature Protocols 6, 1060-1083. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry.
Zhang, Abdallah, Williams, Harrad, Chipman, Viant, 2016, Chemosphere 144, 1996-2003. Gene expression and metabolic responses of HepG2/C3A cells exposed to flame retardants and dust extracts at concentrations relevant to indoor environmental exposures.
Kordalewska and Markuzewski. 2015, Journal of Pharmaceutical and Biomedical Analysis 113; 121-136. Metabolomics in cardiovascular diseases.
Laverty et al., 2011, Br. J. Pharmacol. 163, 675-693. How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?
Southam, Weber, Engel, Jones, Viant, 2017, Nature Protocols 12, 310-328. A complete workflow for high-resolution spectral-stitching nanoelectrospray direct-infusion mass-spectrometry-based metabolomics and lipidomics.
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