Characterization of biological effects of KdPT on epithelial barrier function and wound healing

• Applicant: Professor Dr. Markus Böhm
• Subject Area: Gastroenterology ; Dermatology
• Term: from 2007 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 50787304

The treatment options for inflammatory bowel diseases are still limited. Previously, we could identify an anti-inflammatory tripeptide derivative of alpha-melanocyte-stimulating hormone, Lys-d-Pro-Thr (KdPT), with promising protective effects in various experimental mouse models of colitis. Based on these pioneering results a phase II multi-center clinical trial is currently conducted in patients with colitis ulcerosa. Notably, the anti-inflammatory effects of KdPT are not limited to the gut. We could show that KdPT suppresses canonical NF-KappaB signalling in SZ95 sebocytes, an immortalized human epithelial sebocytes cell line frequently used as an vitro model of acne, the most common inflammatory skin disease. Interestingly, KdPT further increased proliferation and augmented barrier function of intestinal epithelial cells possibly by modulating expression and/or localization of distinct Tight Junction (TJ) proteins.Based on these encouraging findings we want to decipher in the present research project (1) the molecular mechanism by which KdPT increases intestinal barrier function. (2) We will investigate if the peptide in vivo promotes healing of mechanically-induced colonic wounds employing murine coloscopy. (3) To test as to whether KdPT promotes wound healing in the skin in an inflammatory setting we will investigate the impact of the peptide in presence of IL-1beta and TNF-alpha on human epidermal keratinocytes as well as in 3D human skin equivalents. (4) Finally, the effect of KdPT on barrier function readouts, expression or localization of TJ proteins, and NF-KappaB activation will be examined in human epidermal keratinocytes in presence of the above proinflammatory cytokines. The last objective will be largely facilitated by sharing experimental methods between the two interdisciplinary parts of the project. Taken together, these preclinical experiments are believed to provide a very promising base for the further exploitation of KdPT in the field of both gastroenterology and dermatology.

• DFG Programme: Research Grants
• Participating Person: Dr. Dominik Bettenworth