Congenital lower urinary tract obstruction, either functional or anatomical, is a serious situation with life-long morbidity and high mortality rates. Neural tract defects such as spina bifida, meningocele, are the most common functional obstruction caused by detrusor sphincter dyssynergy, with an incidence of 0.1-5 per 1,000 births.
Anatomical obstacles are due to congenital urethral valves, urethral atresia and Prune-Belly syndrome, with an incidence of 2.2 per 10,000 births. Such obstacles in the urinary tract cause high pressure in the bladder or renal pelvis. As a consequence, patients will develop bladder fibrosis, reduced capacity and renal insufficiency if this condition remains untreated.
Bladder fibrosis is a remodelling process after tissue damage, where epithelial cells are replaced by fibroblasts and possibly collagen without normal organ function. Studies in the liver and lungs have shown that the activity of different signalling pathways changes and exacerbates fibrosis. However, there is limited knowledge about bladder fibrosis, and there is as yet no conservative treatment for bladder fibrosis. An operation to enlarge or replace the bladder is often unavoidable for children with severe bladder fibrosis.
Fibrosis is the final step of tissue damage, under which TGF-β1 is known to play a critical role in this process. Together with BMPs and other cytokines, TGF-βs are members of the TGF-β super family. The balance between active TGF-β1 and the protein substance BMP7, which is found in normal tissue, changes to activated TGF-β1 during inflammation and fibrogenesis. Studies have shown that BMP7 counteracts the TGF-β1 activity during fibrosis in different organs, including the lungs, heart and kidneys.
This project aims to delay and possibly stop or perhaps even repair the bladder damage by means of BMP7. BMP7 is found naturally in the body, but may be added from the outside to prevent the formation of scar tissue. The aim is to further develop the results of an animal model into a potential clinical trial.
Project responsibility: MD, PhD Yutao Lu
Principal supervisor: Professor, DMSc L. Henning Olsen
Co-supervisor: Associate Professor, MSc, PhD Rikke Nørregaard
Co-supervisor: Professor Paul Austin, MD, PhD, Washington University, St. Louis
Co-supervisor: Professor, DMSc Jens Christian Djurhuus
