About our research

The etiology of Primary Sclerosing Cholangitis (PSC) is not known. Genetic factors are likely to play an important role in disease development, as shown by an increased risk of disease in first degree relatives of patients with PSC. By studying disease genes and their function, the mechanisms by which PSC develop and eventually may be treated can be defined. This has been the basis for the first 3-year work package in the functional genetics group at the Norwegian PSC Research Center (2008-2011). To focus the expansion of activity, the local undertakings in projects of the group were slowly being directed in three major directions throughout 2010 (see figure below):

Genetic susceptibility: During 2010, PhD students Trine Folseraas and Sigrid Næss took the lead in the genetic studies in PSC following the completion of the PhD projects of Espen Melum and Johannes Hov. Main ongoing projects in 2010 were an extended analysis of the existing GWAS data; the Immunochip project; a collaboration with groups working on primary biliary cirrhosis to detect genetic factors responsible for cholestatic itching as well as several projects refining the genetic associations in the HLA complex in PSC. Throughout 2011 these latter activities will be integrated with activities aimed at defining the specificity of the T-cell reactivity in PSC with Johannes Hov in charge of several of subprojects. During 2010 the genetics sub-group also initiated preparations for whole-exome sequencing projects in families with >3 PSC affected members and the final preparations for the UK and US based GWAS to be performed in 2011 were also performed.

Biomarker discovery: Anders Holm was employed as post doc from 2011 to support proteomic aspects of "disease activity markers" in PSC. Disease activity markers may guide prognostic considerations and serve as surrogate markers for effects from interventions (e.g. therapeutics). The protein level work will be integrated with transcriptomic (Trine Folseraas) and micro-RNA (performed by collaborator) analyses performed throughout 2010 and is partly founded on insights obtained from the genetic studies. Diagnostic aspects will be restricted to the early detection of PSC in inflammatory bowel disease (IBD), and approximately 500 Norwegian patients with a 20 year history of IBD are currently being screened with magnetic resonance cholangiography as part of this. 

Bile duct pathobiology: Alexey Shiryaev was employed as post doc in 2010 to facilitate studies into disease mechanisms based on genetic findings. The initial work has gone into establishing tools for in vitro and in vivo experiments, including the establishment of cholangiocyte isolation protocols (allowing for culturing as well as transcriptome analysis of freshly isolated cholangiocytes) and activities to support the development of a "cholangiocyte specific Cre"  (a transgenic mouse strain that will allow for deletion of particular genes in cholangiocytes only). The model will be used to study the influence of selected PSC susceptibility genes on cholangiocyte function. Espen Melum at Harvard is currently performing work in mice not directly related to PSC, but will strengthen the activities of this work package upon return in 2012, including the ultimate establishment of relevant animal facilities in the group. 

Figure: The activities of the functional genetics group were throughout 2010 directed in three directions to expand according to the strategy yet restricting the focus.