Nonalcoholic steatohepatitis (NASH) is the most extreme form of nonalcoholic fatty liver disease that fat accumulate along with inflammation in and around the liver cells. There is currently no approved therapy for NASH despite the disease affects 2-5% of the adult population and progresses to cirrhosis in 15-20% of affected subject in UK. Patients with NASH are at significantly greater risk of morbidity and mortality than those with simple fatty liver (steatosis). However, what determines the progression to NASH is not clear and these groups can only be differentiated by liver biopsy, a costly and potentially risky invasive procedure. Our preliminary observations have led to a HYPOTHESIS that THE PATHOGENESIS OF NASH IS DRIVEN BY A COMBINATION OF TRANSCRIPTS INTERACTING WITH THE LIVER LIPIDS AND METABOLITES.
Therefore, the GOALS of this proposal are to understand: i) which transcripts, lipids and metabolites determine the progression from steatosis to NASH; ii) how these factors cross talk with each other, especially in triggering liver inflammation; iii) whether a systematic model is capable to illustrate/predict the pathophysiological profile of the disease progression. Our long term objective is to define the mechanisms of NASH progression to inform cost effective prevention and treatment strategies in UK. The current proposal view this via integrating multi-dimensional omic datasets to develop a model that associate with and/or predict disease progression, focusing on defining the cross-talk between transcripts, lipids and metabolites in NASH characterized by liver inflammation.
The student will develop quantitative (at Cardiff) and wet-lab skills (at Exeter) through i) performing a causal modeling based on an integrated analysis of omic datasets (each sample: ~25000 transcripts by RNA-seq, ~5000 lipids & metabolites, ~100 clinical variables) from a liver biopsy cohort including 100 subjects across different stages of NASH; ii) using systems biology approaches for metabolic modeling and biomarker identification in NASH. Based on the integrated transcriptome, metabolome, lipidome and clinical data, a recently established genome-scale metabolic model will be adopted and employed as a platform for tissue-specific modeling; iii) validating the model networks as well as potential molecular markers in an independent cohort at University of Exeter (12 liver samples, NASH activity score 0-5) by QPCR, western blotting and cell culture. The cross talk between liver & adipose tissues indicating by the model could be further explored based on the time frame agreed by the student.
The student will transfer the knowledge/techniques from one lab to the others, broaden her/his horizons and develop a long-term partnership across GW4 communities (Vide infra, page 8). The impact of the research will be maximized through publications in decent journals, presentations at specialist conferences, social media and lab website.
Funding: This studentship is funded through GW4BioMed MRC Doctoral Training Partnership. It consists of full UK/EU tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£14,553 p.a. for 2017/18, updated each year).
Additional research and training funding is available over the course of the programme. This will cover costs such as research consumables, courses, conferences and travel. Additional competitive funds are available for high-cost training/research.
The research project listed is in competition with 40 other studentship projects available across the GW4 BioMed MRC Doctoral Training Partnership. Up to 8 studentships will be awarded to the best applicants.
You will need to complete both an application to the GW4 BioMed MRC DTP for an ‘offer of funding’ and to Cardiff University for an ‘offer to study’.
Offer of Funding Applicants should apply for funding via the centralised online application form, between 11th May and 9.30am 8th June 2017. (Click ’apply online’ below).
Offer of Study Applicants should also submit an application for postgraduate study via the Cardiff University Online Application Service https://tinyurl.com/klqxt3s
Applicants should select Doctor of Philosophy (Medicine), with a start date of October 2017.
In the research proposal section of your application, please specify the project title and supervisors of this project and copy the project description in the text box provided. In the funding section, please select “I will be applying for a scholarship / grant” and specify that you are applying for advertised funding from GW4 BioMed MRC DTP.
If you are applying for more than one Cardiff University project, please note this in the research proposal section.
Academic criteria: Applicants must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of medical sciences.
English requirements: If English is not your first language you will need to meet the English language requirements of Cardiff University. This will be at least 6.5 in IELTS or an acceptable equivalent.
Residency: Applications are welcome from both UK and EU candidates; however, as a consequence of the EU referendum result, final award decisions will depend on the outcomes of the UK/EU negotiations.