Ongoing Projects

Our Functional Urology Group investigates the molecular mechanisms underlying the functional and morphological changes in the bladder during LUTD. Our comprehensive transcriptome sequencing, the first of its kind, of human bladder biopsy samples from patients with benign prostatic obstruction revealed activation of immune response and proliferative signalling pathways, and suggested an increasing involvement of regulatory small non-coding miRNAs in the control of bladder function. We identified 3 mRNA- and 3 miRNA-biomarker signatures sufficient to discriminate between bladder functional states, validated them in a blinded study and showed the normalization of their expression in patients whose bladder function improved after deobstruction. Early identification of structural changes in the bladder during LUTD can optimize the timing of treatment. We are in the possession of a unique collection of human biopsy samples from patients with well-characterized bladder functional phenotypes before and after deobstruction surgery. Many different underlying pathogenetic mechanisms of similar symptomatic complexes necessitate different therapeutic strategies. The functional and molecular progression of LUTD in the mouse models of pBOO, SCI, and MS can be monitored longitudinally, in different phases of the disease characterized by distinct functional phenotypes. Genes identified in the animal trials can be compared with the human biopsy data to further validate the most promising markers and pathways. Our approach relies on generation and analysis of big gene expression data to reveal the triggers of LUTD. To achieve our goal of unbiased classification of LUTD and identification of molecular drivers of pathologic bladder remodelling, we apply machine learning algorithms to the transcriptome data, clinical information from the patients, and relevant animal models.
Funding: Swiss National Science Foundation SNF (Grant Nr 310030_175773/1, 2018-ongoing)

Lower urinary tract dysfunction (LUTD) can develop as the result of bladder outlet obstruction (BOO) and in neurological diseases including spinal cord injury (SCI). A dangerous and potentially life threatening form of neurogenic LUTD is detrusor sphincter dyssynergia, where the detrusor and sphincter muscle contractions are uncoordinated, leading to high pressure voiding, detrusor overactivity and development of residual urine. The ensuing urinary tract infections combined with the high intravesical pressure, if left untreated, cause renal reflux and kidney failure. Similarly, in BOO profound remodelling ultimately leads to the loss of bladder function. It is very difficult to conduct longitudinal studies of these changes in human patients, because development of LUTD is a long process. Therefore, we resorted to animal models of SCI- and BOO-induced bladder dysfunction to study molecular changes in the bladder as disease progresses. Urodynamic investigation is the only objective method to assess bladder function, and we established urodynamic investigations combined with electromyography (EMG) to record the activity of the external urethral sphincter in fully awake mice. This innovative methodology allows the recording of non-voiding contractions equivalent to detrusor overactivity in humans and the appearance of DSD. We are monitoring functional and molecular progression of obstructive and neurogenic LUTD in the mouse models of partial bladder outlet obstruction as well as SCI in different phases of disease characterised by distinct functional phenotypes. This research has high translational potential, which makes it an essential addition to our on-going studies of the mechanisms of bladder remodelling during LUTD in humans. 
Funding: Swiss National Science Foundation SNF (Grant Nr 310030_175773/1, 2018-ongoing)

We are running collaborative projects with the University of Oslo, Norway, and Paracelsus Medical University, Salzburg, Austria, investigating the gene expression changes in the neurogenic bladders of human SCI patients and in rats with experimentally-induced neurogenic bladder dysfunction. Both studies examine the effects of treatments (early Onabotulinumtoxin A injections into detrusor of humans with SCI, and a leukotriene receptor antagonist in rats) on the bladder function and expression of genes indicative of the activation of specific pathways involved in the organ remodelling. We conduct transcriptome and proteome analysis to describe the SCI-induced short and long term molecular changes the bladder tissue and the spinal cord, and assay the treatment effects. The human longitudinal data obtained by repeated biopsy collection up to 1 year after SCI is unique and will provide an invaluable control for the animal models of different species, allowing to identify the best-suited candidates for translational research.
Funding: Wings for Life – Spinal Cord Research Foundation (2019-ongoing)

Bladder outlet obstruction is characterized by an increased outlet resistance leading to an elevated detrusor pressure and decreased urinary flow during voiding. Urodynamic examination remains the gold standard procedure for the diagnosis of obstruction-induced LUTD, but it is an invasive procedure, associated with risks of haematuria and urinary tract infection. Therefore, effort is being made to find non-invasive parameters for the diagnosis of BOO and other LUTD. Urine is easy to collect, making it an attractive source of potential biomarkers. It contains small molecule metabolites and a considerable number of proteins and nucleic acids, both free and packaged in urinary extracellular vesicles (uEVs). This project examines the potential of urine, a good source of circulating miRNAs, which can be used as disease biomarkers.  Urinary miRNA assessment is non-invasive, and offers advantages over urodynamics and other methods, requiring special skills and trained personnel. In order to facilitate the assessment of the bladder function, relevant for diagnostic of LUTS and obstruction, we developed an optimized ultracentrifugation and size exclusion chromatography approach for highly reproducible isolation for 50-150 nm urinary vesicles, corresponding to the exosomes, from urine. We are investigating the urinary miRNA signatures able to discriminate between controls and the patients with BLUTD and NLUTD. The panel of representative miRNAs is further explored to develop a non-invasive diagnostic test for bladder outlet obstruction and neurogenic bladder dysfunction.

Our comprehensive transcriptome analysis showed that TNF- signalling contributes to the loss of contractility during Benign Prostatic Obstruction (BPO). We hypothesised that a compensatory up-regulation of miRNAs, targeting important hubs of TNF- signalling pathways might mitigate this process in order to prevent bladder decompensation. We developed and experimentally validated bioinformatic tools to predict the impact of dysregulated miRNAs on cell signalling relevant for disease development. Now we evaluate the significance of the disease-inhibited miRNAs to compensate the aberrant disease-mediated signalling.  In this project we address the role of TNF- in obstructed bladders, focusing on its interplay with miRNAs, which can both regulate gene expression and act as biomarkers of the functional state of the organ. We are investigating the molecular mechanisms of miRNA down-regulation, and are seeking means to preserve the levels of important miRNAs, capable of attenuating pathologic organ remodelling. The potential of down-regulated miRNAs to counteract the aberrant disease-mediated signalling is a highly innovative paradigm. Analysis of miRNA promoter sequences and uncovering the mechanism of their inhibition will contribute to our understanding of bladder hypertrophy and decompensation.