MRC DiMeN Doctoral Training Partnership: Antiretroviral-induced metabolic toxicity: Role of adipose- miRNAs as mechanistic regulators and toxicity biomarkers
Dr S Pushpakom
Prof M Bushell
Prof Sir M Pirmohamed
Background: Diabetes, obesity and cardiovascular disease (collectively called cardiometabolic disease) remain a major public health problem worldwide. Cardiometabolic disease can also develop as a result of drug treatment; for example, antiretroviral drugs which are used in the treatment of HIV/AIDS result in insulin resistance and lead to increased risk of cardiometabolic disease. Changes in adipose tissue gene expression and adipokine secretion are pathogenically important in the development of cardiometabolic disease. Micro-RNAs (miRNAs) are small non-coding RNA molecules which play an important role in the post-transcriptional regulation of gene expression. Adipose-derived miRNAs have been shown to regulate insulin levels, secretion of adipokines and control the whole body glucose homeostasis (Nature, 2017); however, little is known about their role in drug-induced cardiometabolic toxicity. With this PhD project, we seek to undertake a translational study using cellular models and clinical samples to obtain mechanistic information about the role of adipose-miRNAs in drug-induced cardiometabolic disease.
Novelty: Tissue-derived miRNAs are mechanistically important in the pathogenesis of disease conditions such as diabetes, heart disease and cancer. They may also serve as biomarkers for early disease prediction (diagnostic); treatment response (prognostic); and, stratification of disease, thereby allowing personalisation of therapy (Personalised medicine).
Approach: This project will undertake global miRNA profiling of primary human adipocyte models to identify miRNAs that are differentially regulated by antiretroviral drugs. The project will link to a drug safety clinical trial in HIV patients (TAILoR trial; Pushpakom et al, 2015) to undertake validation of the top hit miRNAs in serum samples obtained from HIV patients with or without insulin resistance. Changes in miRNA levels in the serum will be correlated against patients’ clinical, biochemical and imaging (MRI) data to determine the mechanisms important in drug-induced cardiometabolic toxicity. Bioinformatic methods will be used to construct miRNA regulatory networks and identify the putative gene targets for the top hit miRNAs. Functional knockdown assays will be used to elucidate their role in adipocyte function, insulin signalling and glucose homeostasis.
Research supervision and training
The proposed study is a collaborative project between the MRC Centre for Drug Safety Science (CDSS) and the Wolfson Centre for Personalised Medicine, University of Liverpool (where Dr Pushpakom is based), and the Cancer Research UK Beatson Institute (Prof Bushell), Glasgow. This studentship will provide a unique training opportunity in the molecular and bioinformatic investigation of the basis of drug-induced metabolic toxicity by a highly experienced supervisory team with complementary research skills. Training will include advanced cell culture methods; metabolic assays; miRNA transcriptomic profiling in both in vitro and clinical samples; bioinformatic data analysis; multi-omic integration of miRNA data sets with clinical trial data; and, functional miRNA assays.
The student will be primarily based in the MRC CDSS and The Wolfson Centre for Personalised Medicine, which are internationally recognised centres of excellence for drug safety research and implementation of personalised medicine. They will also have an opportunity to train in the Beatson Institute, which is one of Cancer Research UK’s core-funded institutes carrying out a programme of world-class science research.
Dr Sudeep Pushpakom: https://www.liverpool.ac.uk/translational-medicine/staff/sudeep-pushpakom/ Prof M Bushell: http://www.beatson.gla.ac.uk/Cancer-Metabolism-Growth-and-Survival/martin-bushell.html
Prof Sir M Pirmohamed: https://www.liverpool.ac.uk/translational-medicine/staff/munir-pirmohamed/
MRC Centre for Drug Safety Science: https://www.liverpool.ac.uk/drug-safety/
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Stipend at national UKRI standard rate
Research training and support grant (RTSG)
Studentships commence: 1st October 2019.
To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: https://goo.gl/8YfJf8
Pushpakom SP et al. Telmisartan reverses antiretroviral-induced adipocyte toxicity and insulin resistance in vitro. Diab Vasc Dis Res. 2018;15(3):233-242. doi: 10.1177/1479164118757924
Pushpakom SP et al. Telmisartan and Insulin Resistance in HIV (TAILoR): protocol for a dose-ranging phase II randomised open-labelled trial of telmisartan as a strategy for the reduction of insulin resistance in HIV-positive individuals on combination antiretroviral therapy. BMJ Open. 2015; 15;5(10):e009566. doi: 10.1136/bmjopen-2015-009566.
Lu WT et al. Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair. Nat Commun. 2018 Feb 7;9(1):532. doi: 10.1038/s41467-018-02893-x