The study focuses on the development of Cajal-like cells during pregnancy in a pig model.

Cajal-like cells are attributed to a pacemaker-like function and are found in several parts of the body.

The same pig model will be used to study the development of aquaporins - proteins that are responsible for transporting water - both in the kidney but also in the ureter and bladder. The idea behind this part of the project is to identify whether the aquaporins are expressed in the urothelium (or possibly deeper in the tissue), together with whether this expression changes during the gestation period. In rodents, an upward adjustment of some of the aquaporins has been seen as a result of dehydration or obstruction, and it could be that this is also the case with urethral valves in boys. The latter group is part of the clinical study of video-urodynamic examinations.

In connection with this, a collaboration has been established with the paediatric urology departments at Great Ormond Street Hospital (GOSH) London, Ghent, Utrecht & Amsterdam. A clinical database is planned for this condition.

Project responsibility: Lotte Kaasgaard Jakobsen

Principal supervisor: Professor, Consultant, DMSc, PhD Henning Olsen

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

We know that children and young people enter puberty earlier than their grandparents did just 50-100 years ago. However, it is not immediately clear whether the average puberty age is continuing to fall, what the cause could be in this case and whether early or late puberty has importance for our health later in life.

In animal experiments it has been shown that exposure to endocrine disrupting chemicals in prenatal life can play a crucial role in pubertal development, but the correlation has never been confirmed in studies on humans. We therefore wish to study the extent of three different factors with potential endocrine disrupting effects - and these are: ingestion of headache medication during pregnancy; the use of hormonal treatment and artificial fertilization to achieve pregnancy; and the content of endocrine disrupting substances (PFCs) in the mother's blood during pregnancy -and whether these alter the age of puberty and the first part of puberty in adolescents. In 2002-2003, blood samples were taken from a group of pregnant mothers who were also interviewed about lifestyle and medicine consumption. 22,550 children born to these mothers have responded to a detailed questionnaire on their pubertal development every six months since the age of 11. In other words, we collect information about their pubertal development while this is happening, and by using this we are able to examine the above-named correlations.

My project will contribute to existing, limited knowledge about pubertal development and potentially identify causes of changes in the age of puberty in Danish adolescents. Studies of the causes of such changes are extremely important, for example as premature pubertal development can be a marker for the development of important diseases such as diabetes, obesity and testicular cancer in adulthood.

Project responsibility: MD, PhD Student Andreas Ernst
Principal Supervisor: Professor Cecilia Høst Ramlau-Hansen, MSc., PhD
Co-Supervisor: Professor Henning Olsen, MD, DMSc
Co-supervisor: Professor Jørn Olsen, MD, PhD

In conventional urodynamics, the urination function is assessed under the artificial replenishment of the bladder and subsequent urination. The examinations can have major consequences for the patients, as many therapeutic decisions are made on the basis of these examinations. However, it is known that the urination function in children is constantly changing throughout their childhood and varies throughout the day. These variations can be picked up by the outpatient examination where the urination function is registered over 24-hours using a small portable unit. The study will compare the two methods and reveal which children benefit from the more resource-intensive ambulatory examination. This is particularly applicable for children with major bladder malformations and children with spina bifida.

Project responsibility: Research Fellow, MD Yutao Lu
Principal supervisor: Professor, DMSc L. Henning Olsen
Co-supervisor: Professor Jens Christian Djurhuus

A widening of the upper urinary tract (hydronephrosis) is one of the most common congenital malformations in urinary tracts. However, only a third of children with this malformation require surgery, while the remaining children must be monitored over a number of years to ensure that the children do not lose their renal function. The purpose of the study is to identify biomarkers in the urine which can help in making decisions about whether to use surgery or not. Urine from these children is systematically collected in a biobank with a view to molecular-biological analysis.

Project responsibility: MD; PhD Mia Gebauer Madsen
Project responsibility: Professor, DMSc L. Henning Olsen
Partners: Associate Professor, PhD Rikke Nørregaard