Changes of microRNA Expression in Obstructive and Neurogenic Bladder Dysfunction

Study Overview
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Brief Summary
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Patients with obstructive or neurogenic lower urinary tract disease will be invited to participate. Upon agreement they will undergo an assessment of bladder function (questionnaires) and bladder biopsies at 2 time-points. Bladder biopsies will be evaluated for molecular changes in the laboratory and compared to the functional findings.By uncovering the molecular similarities and differences between BLUTD and NLUTD, the investigators will elucidate some of the causative factors in the development of these disorders and highlight the impact of myogenic and neurogenic components postulated to be involved. The project involves close collaboration between clinical and basic research.

Detailed Description
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Lower urinary tract dysfunction (LUTD) has multiple causes including bladder outlet obstruction (BOO) as a result of benign prostatic hyperplasia (BPH) and neurological diseases including spinal cord injury (SCI). Manifestations of LUTD include storage symptoms such as increased daytime frequency, nocturia, urgency and urinary incontinence and voiding symptoms such as slow stream, hesitancy and incomplete emptying. The consequences of both BOO-induced (BLUTD) and neurogenic LUTD (NLUTD), leading to functional entities including the low compliance high pressure bladder as well as the acontractile high volume low pressure bladder, are believed to share some pathogenetic mechanisms. In a previous project, the investigators have established micro ribonucleic acid (miRNA) and messenger ribonucleic acid (mRNA) expression profiles of several urodynamically defined states of BLUTD. In this follow-up project, the investigators propose to extend these studies, undertaking a comparative miRNA and RNA profiling of BLUTD and NLUTD, and investigate the dynamic alteration of microRNA expression in different functional manifestations of disease. The investigators propose to validate primary gene targets of miRNAs differentially expressed in urodynamically defined states of BLUTD and identify signaling pathways, activated during the progression from hypertrophy to decompensation. Monitoring the reversal of changes in miRNA expression after relief of obstruction and restoration of normal bladder function will help delineate the key BOO-induced miRNAs with regulatory potential. Similarly, the dynamics of miRNA alteration, observed in SCI patients during the development and management of NLUTD should reveal the role of miRNA in gene expression regulation during neurogenic-induced organ remodelling. By uncovering the molecular similarities and differences between BLUTD and NLUTD, the investigators will elucidate some of the causative factors in the development of these disorders and highlight the impact of myogenic and neurogenic components postulated to be involved. The project involves close collaboration between clinical and basic research, and combines the analysis of human biopsy material with in vitro cell-based assays, creating a comprehensive platform for the dissection of molecular mechanisms of LUTD. This project will keep the momentum of the investigators' previous research and contribute to the basic and applied studies into bladder remodeling. It is a logical continuation of their on-going studies of the role of miRNAs in LUT disorders but represents a novel direction of research and has high diagnostic and therapeutic potential.

Official Title
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Changes of microRNA Expression in Obstructive and Neurogenic Bladder Dysfunction Reveal Common Signalling Pathways Relevant for Disease Progression and Recovery

Conditions
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Disorder of the Lower Urinary Tract

Intervention / Treatment
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* Procedure: Bladder biopsy
* Procedure: Urodynamic study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Planned cystoscopy in anesthesia for upper tract stone treatment or microscopic hematuria evaluation (controls) Planned TURP (transurethral prostate resection) (BLUTD) Spinal cord injury (in last 6 weeks) (NLUTD) Prior urodynamic study Informed consent Exclusion Criteria: Age < 18 years old Pregnancy Urinary tract infection History of or current genitourinary tuberculosis, bladder malignancy, radiotherapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Controls<br>No lower urinary tract symptoms undergoing cystoscopy in anesthesia for stone treatment or microhematuria assessment. | Procedure: Bladder biopsy<br>* Small biopsy of the bladder is taken with cold-cup tongs.<br>|
| Spinal cord injury/acontractile<br>Patients with traumatic spinal cord injury (SCI) with no (neither spontaneous nor provoked) detrusor activity during the filling phase of urodynamics. Bladder biopsy 6 weeks after trauma 6 months later urodynamic study and bladder biopsy | Procedure: Bladder biopsy<br>* Small biopsy of the bladder is taken with cold-cup tongs.<br>Procedure: Urodynamic study<br>* Assessment of bladder function through intravesical and intrabdominal pressure measurements according to International Continence Society standards.<br>|
| Spinal cord injury/Detrusor overactivity<br>SCI patients with proven detrusor (urodynamics) overactivity during the filling phase. Bladder biopsy 6 weeks after trauma 6 months later urodynamic study and bladder biopsy | Procedure: Bladder biopsy<br>* Small biopsy of the bladder is taken with cold-cup tongs.<br>Procedure: Urodynamic study<br>* Assessment of bladder function through intravesical and intrabdominal pressure measurements according to International Continence Society standards.<br>|
| Prostatic obstruction/acontractile<br>Low flow to no flow, no measurable detrusor activity on urodynamic evaluation, cystoscopy in line with obstruction. Bladder biopsy at TURP (transurethral resection prostate) 3 months later urodynamic study and bladder biopsy | Procedure: Bladder biopsy<br>* Small biopsy of the bladder is taken with cold-cup tongs.<br>Procedure: Urodynamic study<br>* Assessment of bladder function through intravesical and intrabdominal pressure measurements according to International Continence Society standards.<br>|
| Prostatic obstruction/ obstructed<br>Obstruction according to Schäfer nomogram on urodynamic evaluation. Bladder biopsy at TURP 3 months later urodynamic study and bladder biopsy | Procedure: Bladder biopsy<br>* Small biopsy of the bladder is taken with cold-cup tongs.<br>Procedure: Urodynamic study<br>* Assessment of bladder function through intravesical and intrabdominal pressure measurements according to International Continence Society standards.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Establishment of mRNA targets and pathways defining a disease state and/or potentially amendable to pharmacological evaluation. | Next generation sequencing of bladder wall tissue to determine changes in mRNAs and their targets and pathways | 8 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bladder, neurogenic lower urinary tract dysfunction, benign prostatic obstruction