2017 research grant award spotlight: ellinghaus, “identification of concrete gene targets for therapuetic intervention by characterizing expressional changes in primary sclerosing cholangitis and ulcerative colitis”

Each year, PSC Partners asks research grant awardees to share a lay summary as part of our grant process.  In order to make this information more digestible and shine a light on each individual study, we will share a summary each week (in alphabetical order of the Principal Investigator’s last names).  We welcome your comments or thoughts for the researchers at the bottom of each of these blog posts, and are excited to share this new PSC-related research with you!

Title: Identification of Concrete Gene Targets for Therapeutic Intervention by Characterizing Expressional Changes in Primary Sclerosing Cholangitis and Ulcerative Colitis

Principal Investigator:
David Ellinghaus, PhD, Institute of Clinical Molecular Biology (IKMB), Kiel University, Germany

Brief Lay Summary of Project:
Genome-wide association studies (GWAS) have identified 23 genome-wide significant risk loci for primary sclerosing cholangitis (PSC); however, the PSC-associated genetic variants explain only 5.5-7.3% of variance in PSC heritability. Systematic transcriptome-wide sequencing studies are needed in addition to genetic studies to identify genes and pathways whose gene expression levels are associated with PSC risk. The key goal of this project is to decipher the mechanisms of action of disease-predisposing GWAS loci of the gut-liver axis to identify concrete gene targets for future experimental studies, for example for therapeutic reprogramming of gene expression. To this end we will complement our RNA-Sequencing data for ulcerative colitis (UC) patients and healthy individuals by total RNA-Sequencing of whole-blood samples from PSC patients. Significant gut-liver axis expression-disease associations will then be determined through cross-disease expression analyses. We aim to understand the molecular master switches which lead to rewiring of gene regulatory networks in PSC and UC.

Personal Interest for Project:
The underlying cause of primary sclerosing cholangitis (PSC), and what triggers it, remains a mystery, and patients with PSC also suffer from a highly increased frequency (62-83%) of inflammatory bowel disease (IBD), which is most often classified as ulcerative colitis (UC). As a researcher who is studying the genetics of PSC and UC, I aim to elucidate which molecular-genetic factors are shared and which are not shared between these concomitant diseases. The goal of the proposed research is to identify concrete gene targets for therapeutic intervention by characterizing expressional changes in PSC and UC.