Our November Researcher in Focus is Prof. Ulla Knaus. Ulla is a Professor of Immunobiology in the School of Medicine, University College Dublin. She is supported by a National Children’s Research Centre (NCRC) Paediatric Research Project Grant (along with her co-investigators Prof. Billy Bourke and Dr. Séamus Hussey) to investigate the role of NOX4 in Crohn’s disease.
Crohn’s Disease is an inflammatory bowel disease affecting approximately 500 Irish children under the age of 16. The incidence of Crohn’s Disease in Irish children has doubled since 2005 and continues to rise with over 100 new cases diagnosed each year. It can cause symptoms such as abdominal pain, diarrhoea, fatigue, weight loss and malnutrition.
Long term inflammation within the intestine caused by Crohn’s Disease can lead to scarring of the intestine (intestinal fibrosis). Extensive scarring can lead to intestinal blockages (fibrotic strictures). As Ulla explains “Available treatments aim to reduce inflammation but cannot treat or prevent fibrosis We know that 30% or more of children with Crohn’s disease develop this fibrosis, but it is currently not possible to predict which patients are at risk of this complication. Patients who develop fibrotic strictures need surgery to remove the blockage, and as fibrosis can recur, repeated surgery may be necessary over their life time, with significant impact on patients’ quality of life”.
Ulla is interested in the role of a protein called NOX4 (NADPH oxidase 4) in intestinal fibrosis. NOX4 is an oxidant generating enzyme that is involved in the production of reactive oxygen species (e.g. hydrogen peroxide), a group of highly reactive and unstable molecules derived from oxygen. Reactive oxygen species play an important role in several biological processes including immunity, cell growth, and cell signalling. However, as they are highly reactive, a build-up of reactive oxygen species can lead to cell damage and high levels are associated with several diseases.
Previous studies have shown that NOX4 is involved in the development of fibrosis in the kidney and liver but it’s role in intestinal fibrosis is unclear. Ulla’s research group are investigating whether NOX4 is also involved in the development of intestinal fibrosis and if targeting or inhibiting NOX4 can be used to treat fibrosis in children with Crohn’s disease. Ulla explains further “Our research is geared towards identifying new targets for intervention in childhood inflammatory bowel disease combined with the validation of these targets in preclinical [animal] models. It is usually a long road from discovery and preclinical models to new drug treatments, but the high level of unmet need requires innovative ideas and new approaches. This project hopes to provide a basis for improved disease management and quality of life in patients with Crohn’s disease by evaluating a new treatment modality”.
Her research into inflammatory bowel disease began when she joined the UCD School of Medicine “Working as a locum pharmacist in community and hospital pharmacies exposed me daily to patients and their concerns, challenges and needs. And while I enjoyed the contact and interaction, I was also very curious and wanted to get a more detailed understanding about how a healthy body works and what goes wrong in disease. Research permits combining both of my interests and integrated my group into a global science community working towards the same goals. Since I joined UCD Medicine the focus of my research has shifted towards intestinal disease, in particular inflammatory bowel disease and gut infections. This change in direction is a result of our close collaboration with colleagues in Gastroenterology at Our Lady’s Children’s Hospital Crumlin, paediatric gastroenterologists worldwide and new enabling technologies that promise to accelerate patient-oriented research”
To date, Ulla and her collaborators in paediatric gastroenterology have made significant contributions to the field, including identifying genetic risk factors associated with the development of inflammatory bowel disease “We participated with our colleagues in Paediatric Gastroenterology at Our Lady’s Children’s Hospital Crumlin in international efforts to identify and characterise gene mutations in oxidant-generating enzymes in children diagnosed with inflammatory bowel disease under the age of six. Identifying genetic risk factors is the first step to individualised therapy and improved outcome for patients. In addition, understanding of how the increased risk for developing inflammatory bowel disease correlates to changes in the gut environment has led to the design of a novel gut modifier which is currently evaluated in preclinical colitis models and will hopefully enter clinical studies in the near future”.
Further information on Ulla’s research can be found through the following links:
UCD Website: https://people.ucd.ie/ulla.knaus