Clinical Significance of Local Hypoxia in Inflammatory Bowel Disease

• Applicant: Dr. Moritz Johannes Strowitzki
• Subject Area: General and Visceral Surgery ; Gastroenterology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 402743636

Ulcerative colitis (UC) represents a chronic inflammatory bowel disease with increasing incidence rates. Many patients suffering UC need to undergo surgery due to severe complications of inflammation, or due to colitis-associated cancer. Inflamed bowel mucosa is severely hypoxic, and it has been demonstrated that hypoxia-inducible transcription factors (HIFs: HIF-1alpha and HIF-2alpha) significantly influence mucosal inflammation and fibrosis in UC. Remarkably, activation of HIFs can context-dependently exert anti- or pro-inflammatory effects. Various preclinical animal studies have documented that colitis and bowel fibrosis can be effectively modulated by pharmacological interference with molecular oxygen-sensing pathways. In particular, pharmacological inhibition of HIF proly-hydroxylase enzymes (PHD1-3) leads to enhanced protection of the intestinal barrier, thus alleviating colitis in experimental animal models. However, these findings could not yet be translated into clinical treatment strategies for human UC patients, mostly because the prognostic significance of local tissue hypoxia concerning clinical disease progression has not been investigated so far. The aim of the present research proposal is, therefore, to investigate the clinical significance of local hypoxia in the pathogenesis of UC. In particular, the following topics and goals (Z1-Z4) shall be addressed: (Z1) Measurement of oxygen partial pressures (pO2) and retrieval of intestinal biopsies from UC patients, as well as healthy counterparts during routine endoscopy; (Z2) analysis of tissue stiffness and markers indicating fibrosis and HIF activation within the harvested tissue biopsies; (Z3) correlation of obtained pO2 values with markers for fibrosis and HIF activation and with the clinical disease progression applying stepwise regression analyses; (Z4) validation of clinical data applying a suitable transgenic mouse strain (tetracycline-inducible villin-cre PHD2 shRNA knock out). This system will enable us to regulate HIF activity via the loss of the PHD2 gene specifically within intestinal epithelial cells in order to reflect results obtained from clinical analyses. The expected results should reveal the significance of local tissue hypoxia in clinical disease progression in UC, and serve as a basis to apply markers of intestinal hypoxia for prognosis-prediction and therapy-guidance for UC patients in clinical practice.

• DFG Programme: Research Fellowships
• International Connection: Ireland
• Host: Professor Dr. Cormac Taylor, Ph.D.