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Postdoc Position in Characterization of Non-Alcoholic SteatoHepatitis (NASH) Using Clinical Proteomics and PTMomics

Background:
Non-alcoholic fatty liver disease (NAFLD), and the more necro-inflammatory and progressive NASH, is an emerging disease, highly associated with features of the metabolic syndrome (obesity y, type 2 diabetes/insulin resistance, dyslipidemia). Indeed, many believe that it is a precursor for insulin resistance driven type 2 diabetes. Current estimates suggest that up to 75% or more obese people exhibit NAFLD and of those 20-30% will progress to NASH within approx. ten years. NASH can further progress to cirrhosis and liver failure.

In the near future NASH will become the primary reason for a liver transplant in the US. Currently, there are no approved therapeutics for the treatment of NASH, although several phase 2 and 3 trials are ongoing exploring the efficacy and outcomes of pro-metabolic (GLP-1 receptor agonists, FXR agonists, PPAR agonists), anti-fibrotic (ASK-1 inhibitor, galectin-3) and anti-inflammatory (pan-caspase inhibitor) pathways.
A major challenge for understanding the epidemiology and pathophysiology of NASH, as well as clinical trial enrolment and therapeutic efficacy assessments, is that NASH is currently diagnosed exclusively via a liver biopsy. Thus, identification of circulating markers that are able to predict NASH or the progression of NASH is paramount. Such panels comprised of standard analytes exist already (e.g., APRI, FIB-4 scores), and can be paired with imaging, but these lack a degree of precision, do not identify patients with rapidly progressive NASH, and are not currently considered gold standards by regulatory agencies. As fibrosis is the strongest predictor of mortality associated with NASH, a circulating marker of hepatic fibrosis that correlates with NASH and identifies rapidly progressing liver damage would be of extremely high value.

Also, there is a lack of understanding of the pathogenesis of NAFLD/NASH at the molecular level. Thus investigation of signal transduction pathways important for the development of NAFLD/NASH will aid in understanding the diseases and develop efficient treatments for the diseases.

Therefore the proposed study, using a thorough clinical proteomic and post-translational modification specific proteomics (PTMomics) analysis, should reveal novel insight into the pathophysiology of NAFLD/NASH and potentially even lead to new therapeutic targets and novel biomarkers for the diseases.

Main objectives of the postdoc project (three years):
• To identify circulating proteins (or specific PTMs) that correlate with key features of liver histopathology, primarily fibrosis, inflammation and/or hepatocyte ballooning, in the context of NASH in rodent and/or hepatocellular or liver tissue ex vivo models.
• To explore the biological mechanism/s of action of key factor/s in the pathogenesis or resolution of NASH in in vitro and/or in vivo models.
• To validate these factor/s in human clinical cohorts to determine their predictive validity in identifying NASH patients and/or with NASH resolution in clinical trial cohorts or subsets of human subjects.
• To perform methodological developments within the clinical proteomics field and in PTMomics characterization of cellular signalling pathways.

Location of the project:
The project is a joint project between the research group of Professor Martin R. Larsen, Department of Biochemistry and Molecular Biology at the University of Southern Denmark, the Danish Diabetes Academy and the company MedImmune.

The Larsen research group is part of the Protein Research Group (PRG) at the University of Southern Denmark (SDU) in Odense, Denmark. Odense is located about one hour from the main capital of Denmark, Copenhagen. The PRG was founded 43 years ago by the recognized protein and biological mass spectrometry researcher Professor Peter Roepstorff and is internationally recognized for their contributions within biological mass spectrometry, proteomics, biomedical research and clinical proteomics. Today the PRG consist of a large research environment with nine individual research groups and more than 60 scientists, postdocs and students who share facilities and research environment. The PRG has the newest mass spectrometers for biological mass spectrometry applications including two Fusion Lumos, three Q-Exactive HF and one Q-Exactive HFX. In addition, the PRG has a large fully equipped protein chemistry/proteomics laboratory, cell laboratory facilities and bioinformatics that will be available for the present project.

The Larsen Group has for the past 20 years developed a large number of methods for assessment of post-translational modification (PTMs) in proteomics, including the Titanium Dioxide method (Larsen MR et al., Mol. Cell. Proteomics 2005) used by many research groups worldwide for isolation of phosphorylated peptides for characterization of signal transduction pathways in mammalian systems. The Larsen group research focus is centered on investigation of the role of PTMs in system biology and biomedicine and development of new innovative methods for assessment of PTMs in biological samples. The Larsen group has a significant amount of national and international collaborations and is publishing in higher ranging journals.

MedImmune is the global biologics research and development arm of AstraZeneca, a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of small molecule and biologic prescription medicines. MedImmune is pioneering innovative research and exploring novel pathways across Oncology, Respiratory, Cardiovascular & Metabolic Diseases, and Infection and Vaccines.

The candidate will be affiliated with the Danish Diabetis Academy which will ensure a thorough education in diabetes and related diseases through access to various courses held by the Academy.

Qualifications:
A successful candidate would have a PhD degree in biochemistry, cell biology, molecular biology, proteomics or a related field and is highly motivated and innovative. A candidate with significant experience in functional proteomics, post-translational modification analysis, LC-based mass spectrometry and bioinformatics is preferable. However, knowledge in diabetes and NASH diseases is a significant merit. Excellent communication and writing skills and an ability to interact socially and scientifically with other laboratory members and collaborators are essential. Previous postdoc experience and a strong publication record are also strong merits.

For further information please contact
Professor Martin R. Larsen, PhD, SDU, e-mail: mrl@bmb.sdu.dk
MedImmune, Dr Christopher Rhodes, PhD, e-mail: rhodesc@MedImmune.com.


Application, salary etc.

The successful applicant will be employed in accordance with the agreement between the Ministry of Finance and AC (the Danish Confederation of Professional Associations). Please check links for more information on salary and taxation.

The following documents must be submitted with your electronic application, and written in English:

• CV including date of public thesis defense and previous positions
• Complete list of publications
• Statement of research interests and previous achievements (max. one page)
• Signed letters of reference from at least two senior researchers (scanned copies acceptable). Should your referees wish to send their letters directly to us, please have them use e-mail: anc@sdu.dk mentioning your name and the title of the position in the subject line. And please note that these also need to reach us before deadline.

The position is limited to a duration of three years.

Shortlisting may be used in the assessment process.

Incomplete applications and applications received after the deadline will neither be considered nor evaluated.

To qualify you must have passed a PhD or equivalent. Applications will be assessed by an expert assessor/committee. Applicants will be informed of their assessment by the university.

The University wishes our staff to reflect the diversity of society and thus welcomes applications from all qualified candidates regardless of personal background.

Applications must be submitted electronically using the link "Apply online". Attached files must be in Adobe PDF or Word format. Each box can only contain a single file of max. 10 Mb. We strongly recommend that you read How to apply before you apply.

Further information for international applicants about entering and working in Denmark.

Send application
Deadline 2019-Mar-01

You can apply for the job at The Faculty of Science by completing the application form

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