Control Of Bladder Function Research Articles

Effect of diabetes on mechanisms controlling bladder function

Effect of diabetes on mechanisms controlling bladder function

Imaging neuro-urodynamics of mouse major pelvic ganglion using a micro-endoscopic approach.

Post-ganglionic neurons of the autonomic nervous system lie outside of the central nervous system and innervate specific target effectors such as organs or glands. The major pelvic ganglion (MPG) is one such ganglion that plays a significant role in controlling bladder function in rodents. However, due to technical and physical constraints in recording electrophysiological signals from these neurons in vivo, the functional neural activity in MPG is mostly unknown. Transgenic animal models expressing genetically encoded calcium indicators now provide opportunities to monitor the activity of populations of neurons in vivo to overcome these challenges related to traditional electrophysiological methods. However, like many peripheral neurons, the MPG is not conducive to conventional fluorescent microscopy techniques, as it is located in the pelvic cavity thus limiting robust optical access by benchtop microscopes. Here, we present an endoscopic approach based on a custom miniscope system (UCLA V3) that allows for effective in vivo monitoring of neural activity in the MPG for the first time. We show that our imaging approach can monitor activity of hundreds of MPG neurons simultaneously during the filling and emptying of the bladder in urethane-anesthetized transgenic mouse line expressing GCaMP6s in cholinergic MPG neurons. By using custom analysis scripts, we isolated the activity of hundreds of individual neurons and show that populations of neurons have distinct phasic activation patterns during sequential bladder filling and voiding events. Our imaging approach can be adapted to record activity from autonomic neurons across different organs and systems in both healthy and disease models.

Proper wiring of newborn neurons to control bladder function after complete spinal cord injury

Activation of endogenous neurogenesis by bioactive materials enables restoration of sensory/motor function after complete spinal cord injury (SCI) via formation of new relay neural circuits. The underlying wiring logic of newborn neurons in adult central nervous system (CNS) is unknown. Here, we report neurotrophin3-loaded chitosan biomaterial substantially recovered bladder function after SCI. Multiple neuro-circuitry tracing technologies using pseudorabies virus (PRV), rabies virus (RV), and anterograde adeno-associated virus (AAV), demonstrated that newborn neurons were integrated into the micturition neural circuits and reconnected higher brain centers and lower spinal cord centers to control voiding, and participated in the restoration of the lower urinary tract function, even in the absence of long-distance axonal regeneration. Opto- and chemo-genetic studies further supported the notion that the supraspinal control of the lower urinary tract function was partially recovered. Our data demonstrated that regenerated relay neurons could be properly integrated into disrupted long-range neural circuits to restore function of adult CNS.

MORPHOFUNCTIONAL AND CLINICAL SIGNIFICANCE OF THE INTERSTITIAL CELLS OF CAJAL IN THE URINARY BLADDER (REVIEW ARTICLE)

The therapy of symptoms of the lower urinary tract that in most cases are caused by benign prostatic hyperplasia is one of challenges for modern medicine. Knowing the origin of bladder muscle hyperactivity will promote the treatment in this group of patients. The studies of interstitial cells of Cajal in the urinary bladder open up new opportunities to widen our understanding of bladder physiology. The purpose of this study is to conduct an analytical review of the literature on the role of interstitial cells of Cajal in the physiology of the urinary bladder. We investigated the current literature highlighting the morphological and physiological significance of interstitial cells of Cajal in the urinary bladder. Interstitial cells of Cajal are in close proximity to muscle cells, vegetative nerve endings and urothelial cells. There is increasing evidence that interstitial cells of Cajal play a role in the development of lower urinary tract symptoms. Interstitial cells of Cajal may be responsible for generating electrical potentials and inducing detrusor muscle contractions. New pathomechanisms of the development of bladder hyperactivity were put forward, namely: impairment of spontaneous contractility caused by altered signal transduction of interstitial Cajal cells between nerves and detrusor muscle cells; change in signal transmission through suburothelial interstitial cells of Cajal. The c–kit receptor is not only a marker for identifying these cells, but may also play a critical role in controlling bladder function. Interstitial cells of Cajal, discovered more than 100 years ago, are still remaining a poorly studied object. Having long processes, interstitial cells of Cajal form multiple contacts with smooth muscle and nerve cells, building up a specific network. Current knowledge about interstitial cells of Cajal in the urinary bladder suggest that these cells and c–kit receptors may become a new “target” for the pharmaceutical therapy of lower urinary tract symptoms and overactive bladder.

Postpartum Women with Urinary Incontinence and Low Back Pain

Background: Many women have urinary Incontinence after giving birth. Approximately 36%-44% of postpartum women have urine incontinence symptoms (UI). Incontinence in the postpartum period is often caused by damage to the urethra, the bladder, the nerves that control bladder function, malfunction in the pelvic floor muscles, or all four. Vesical denervation likely causes UI in women who have had a cesarean section by making the detrusor muscle unstable. F.Factors, Surgical Vaginal Birth, and Prenatal Bladder Neck movement owing to dysfunctional Pelvic Floor Muscles (PFM) and weakened Connective Tissue are further risk factors for the development of UI. Joint laxity, weakening of Connective Tissue, Loosened Ligaments and Stretched Abdominal Muscles from the growing uterus all contribute to the typical occurrence of lower back pain (LBP) in women after childbirth. It has been shown that postpartum women who experience low back pain and UI often do so together. Objective: This study aims to determine whether or not Urine Incontinence and Low Back Pain are related in Postpartum Women. Methodology: the study was conducted in Department of Urology at Lady Reading Hospital (LRH) Quota sampling was employed for this analysis. One group consisted of women with low back discomfort after delivery, whereas the other did not. In order to investigate the correlation between UI severity and LBP, participants were given UI questionnaires. Self-administered questionnaires were made available to respondents in English. Because some participants could not read the questionnaires, we had to collect the information from them verbally. Results: Fisher's exact test was used to look at the distribution of ICIQ-UI scores; the p-value was > 0.05 therefore the null hypothesis was not rejected. This meant that there was no correlation between urinary Incontinence and Lower back pain in women postpartum. Conclusion: This Study concludes disproving the hypothesis that UI and postpartum women experiencing low back discomfort. Keywords: Urinary Incontinence UI), Low Back Pain (LBP), Post Partum period. Pelvic Floor Disorders,

Intervention program for women complaining from urinary incontinence at Aga city

Background: Urinary incontinence affect women at any age in which deteriorate their quality of life. Pelvic training to control bladder function at regular time intervals has been demonstrated to be an effective method for treating incontinence. Aim: the study aimed to evaluate the effect of intervention program for women complaining from UI. Study design: A quasi-experimental design was used in this study. Setting: The study was conducted at five outpatient clinics of Aga central hospital, Dakahlia Government, Egypt. Sample: A purposive sample was used to select 354 women divided randomly into study group and control group each of them were 177. Tools: Two tools were used for data collection. 1st tool is a structural interviewing questionnaire: It contained four parts: Part I: Women socio-demographic characteristics. Part II: women’s history. Part III: Women’s knowledge regarding urinary incontinence and pelvic floor muscle exercises. Ⅳ: Women’s reported practice regarding pelvic floor muscle exercises. 2nd tool is Urogenital Distress Inventory (UDI) standardized tool to assess urinary system efficiency.

Remyelination Improves Voiding Dysfunction in a Mouse Model of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Of note, over 80% of MS patients have urinary symptoms as one of their earliest symptoms. Since MS patients often live into older age, urinary incontinence and retention are significant problems affecting their quality of life. Although several studies show that inflammatory-demyelinating animal models of MS develop bladder dysfunction, the confounding influence of systemic inflammation in these models limits potential interpretation on the contribution of CNS-myelination to bladder dysfunction. We sought to address this knowledge gap using the cuprizone model of demyelination and remyelination. C57Bl/6 mice were treated with dietary cuprizone (0.2%w/w) for four weeks to induce demyelination. One group was allowed four additional weeks for recovery and remyelination. We performed voiding spot assay (VSA), urethane-anesthetized cystometry, and CNS-histology to assess demyelination-induced differences in urinary performance. We observed that cortical demyelination causes significant aberrance in voiding behavior (conscious cortical control) characterized by increased micturition frequency and reduced volume per micturition. Interestingly, remyelination restored healthy bladder function. However, there were no significant changes in the cystometric parameters (brainstem reflex) between the treatment groups. While MS is not classically considered a disease of aging, extending the longevity of these patients has not been reciprocated with improved treatments for their most-bothersome conditions, notably urinary symptoms that persist throughout life. Our data represent a novel compelling connection and strong correlation between CNS-myelination and cortical control of bladder function, which has potential implications in MS, aging, and aging-associated neurological disorders.

Endogenously Regenerated Neurons Wire Properly to Control Bladder Function After Complete Spinal Cord Injury

Endogenously Regenerated Neurons Wire Properly to Control Bladder Function After Complete Spinal Cord Injury

Estimation of Bladder Pressure and Volume from the Neural Activity of Lumbosacral Dorsal Horn Using a Long-Short-Term-Memory-based Deep Neural Network

In this paper, we propose a deep recurrent neural network (DRNN) for the estimation of bladder pressure and volume from neural activity recorded directly from spinal cord gray matter neurons. The model was based on the Long Short-Term Memory (LSTM) architecture, which has emerged as a general and effective model for capturing long-term temporal dependencies with good generalization performance. In this way, training the network with the data recorded from one rat could lead to estimating the bladder status of different rats. We combined modeling of spiking and local field potential (LFP) activity into a unified framework to estimate the pressure and volume of the bladder. Moreover, we investigated the effect of two-electrode recording on decoding performance. The results show that the two-electrode recordings significantly improve the decoding performance compared to single-electrode recordings. The proposed framework could estimate bladder pressure and volume with an average normalized root-mean-squared (NRMS) error of 14.9 ± 4.8% and 19.7 ± 4.7% and a correlation coefficient (CC) of 83.2 ± 3.2% and 74.2 ± 6.2%, respectively. This work represents a promising approach to the real-time estimation of bladder pressure/volume in the closed-loop control of bladder function using functional electrical stimulation.

Fatty acid amide hydrolase inhibition normalises bladder function and reduces pain through normalising the anandamide/palmitoylethanolamine ratio in the inflamed bladder of rats.

Fatty acid amide hydrolase inhibition may be used to control bladder function and pain by modulating endocannabinoid levels in cystitis. We studied the effect of the peripherally restricted fatty acid amide hydrolase inhibitor URB937 in bladder reflex activity and bladder pain using the lipopolysaccharide model of cystitis. We also correlated the URB937's effects with tissue levels of the endocannabinoids anandamide and palmitoylethanolamine. URB937 did not change the reflex activity of normal bladders. In inflamed bladders, URB937 had a U-shaped dose-response curve; following an initial cannabinoid receptor type 1-mediated reduction in pain responses and normalisation of bladder reflex activity, URB937 gradually increased both pain responses and bladder reflex activity through the transient receptor potential ion channel subfamily V member 1. Chronic cystitis increased the tissue levels of anandamide and decreased those of palmitoylethanolamine. At the dose that normalised bladder reflex activity and decreased pain responses, URB937 normalised the levels of anandamide and palmitoylethanolamine in the bladder. At high doses that induced excitatory effects, URB937 apparently did not change anandamide and palmitoylethanolamine levels, which therefore were in the range of the inflamed bladder. Fatty acid amide hydrolase inhibition results in complex changes in bladder endocannabinoid levels. The therapeutic effect of fatty acid amide hydrolase inhibitors is not related to increase in anandamide levels but rather a normalisation of the anandamide and palmitoylethanolamine level ratio.

Non-Crh Glutamatergic Neurons in Barrington's Nucleus Control Micturition via Glutamatergic Afferents from the Midbrain and Hypothalamus.

Lower urinary tract symptoms (LUTS) are exceptionally common and debilitating, and they are likely caused or exacerbated by dysfunction of neural circuits controlling bladder function. An incomplete understanding of neural control of bladder function limits our ability to clinically address LUTS. Barrington's nucleus (Bar) provides descending control of bladder and sphincter function, and its glutamatergic neurons expressing corticotropin releasing hormone (BarCrh/Vglut2) are implicated in bladder control. However, it remains unclear whether this subset of Bar neurons is necessary for voiding, and the broader circuitry providing input to this control center remains largely unknown. Here, we examine the contribution to micturition behavior of BarCrh/Vglut2 neurons relative to the overall BarVglut2 population. First, we identify robust, excitatory synaptic input to Bar. Glutamatergic axons from the periaqueductal gray (PAG) and lateral hypothalamic area (LHA) intensely innervate and are functionally connected to Bar, and optogenetic stimulation of these axon terminals reliably provokes voiding. Similarly, optogenetic stimulation of BarVglut2 neurons triggers voiding, whereas stimulating the BarCrh/Vglut2 subpopulation causes bladder contraction, typically without voiding. Next, we genetically ablate either BarVglut2 or BarCrh/Vglut2 neurons and found that only BarVglut2 ablation replicates the profound urinary retention produced by conventional lesions in this region. Fiber photometry recordings reveal that BarVglut2 neuron activity precedes increased bladder pressure, while activity of BarCrh/Vglut2 is phase delayed. Finally, deleting Crh from Bar neurons has no effect on voiding and related bladder physiology. Our results help identify the circuitry that modulates Bar neuron activity and identify subtypes that may serve different roles in micturition.

Activation of the spinal neuronal network responsible for visceral control during locomotion

It has been established that stepping of the decerebrate cat was accompanied by involvement of the urinary system: external urethral sphincter (EUS) and detrusor muscle activation, as well as the corresponding increase of the intravesical pressure. Detrusor and EUS evoked EMG activity matched the limbs locomotor movements. Immunohistochemical labeling of the immediate early gene c-fos expression was used to reveal the neural mechanisms of such somatovisceral interconnection within the sacral neural pathways. Study showed that two locomotor modes (forward and backward walking) had significantly different kinematic features. Combining the different immunohistochemical methods, we found that many c-fos-immunopositive nuclei were localized within several visceral areas of the S2 spinal segment which matched the sacral parasympathetic nucleus and dorsal gray commissure. Cats stepping backward had 4-fold more c-fos-immunopositive nuclei within the ventrolateral part of the sacral parasympathetic nucleus apparently correspondent to the “lateral band” contained cells controlling bladder function. The present work provides the direct evidences of visceral neurons activation depending on the specific of locomotor pattern and confirms the somatovisceral integration carrying out on the spinal cord level.

Simultaneous Measurement of Neuronal Activity in the Pontine Micturition Center and Cystometry in Freely Moving Mice

Understanding the complex neural mechanisms controlling urinary bladder activity is an extremely important topic in both neuroscience and urology. Simultaneously recording of the bladder activity and neural activity in related brain regions will largely advance this field. However, such recording approach has long been restricted to anesthetized animals, whose bladder function and urodynamic properties are largely affected by anesthetics. In our recent report, we found that it is feasible to record bladder pressure (cystometry) and the related cortical neuron activity simultaneously in freely moving mice. Here, we aimed to demonstrate the use of this combined method in freely moving mice for recording the activity of the pontine micturition center (PMC), a more difficultly approachable small region deeply located in the brainstem and a more popularly studied hub for controlling bladder function. Interestingly, we found that the duration of urination events linearly correlated to the time course of neuronal activity in the PMC. We observed that the activities of PMC neurons highly correlated with spike-like increases in bladder pressure, reflecting bladder contractions. We also found that anesthesia evoked prominent changes in the dynamics of the Ca2+ signals in the PMC during the bladder contraction and even induced the dripping overflow incontinence due to suppression of the neural activity in the PMC. In addition, we described in details both the system for cystometry in freely moving mice and the protocols for how to perform this combined method. Therefore, this work provides a powerful approach that enables the simultaneous measurement of neuronal activity of the PMC or any other brain sites and bladder function in freely behaving mice. This approach offers a promising possibility to examine the neural mechanisms underlying neurogenic bladder dysfunction.

Traumatic Brain Injury-related voiding dysfunction in mice is caused by damage to rostral pathways, altering inputs to the reflex pathways

Brain degeneration, including that caused by traumatic brain injury (TBI) often leads to severe bladder dysfunction, including incontinence and lower urinary tract symptoms; with the causes remaining unknown. Male C57BL/6J mice underwent repetitive moderate brain injury (rmdTBI) or sham injury, then mice received either cis P-tau monoclonal antibody (cis mAb), which prevents brain degeneration in TBI mice, or control (IgG). Void spot assays revealed age-dependent incontinence in IgG controls 8 months after injury, while cis mAb treated or sham mice showed no dysfunction. No obvious bladder pathology occurred in any group. Urodynamic cystometry in conscious mice revealed overactive bladder, reduced maximal voiding pressures and incontinence in IgG control, but not sham or cis mAb treated mice. Hyperphosphorylated tau deposition and neural tangle-like pathology occurred in cortical and hippocampal regions only of IgG control mice accompanied with post-traumatic neuroinflammation and was not seen in midbrain and hindbrain regions associated with bladder filling and voiding reflex arcs. In this model of brain degeneration bladder dysfunction results from rostral, and not hindbrain damage, indicating that rostral brain inputs are required for normal bladder functioning. Detailed analysis of the functioning of neural circuits controlling bladder function in TBI should lead to insights into how brain degeneration leads to bladder dysfunction, as well as novel strategies to treat these disorders.

The association of adelmidrol with sodium hyaluronate displays beneficial properties against bladder changes following spinal cord injury in mice.

The disruption of coordinated control between the brain, spinal cord and peripheral nervous system caused by spinal cord injury (SCI) leads to several secondary pathological conditions, including lower urinary tract dysfunction. In fact, urinary tract dysfunction associated with SCI is urinary dysfunction could be a consequence of a lack of neuroregeneration of supraspinal pathways that control bladder function. The object of the current research was to explore the effects of adelmidrol + sodium hyaluronate, on bladder damage generated after SCI in mice. Spinal cord was exposed via laminectomy, and SCI was induced by extradural compression at T6 to T7 level, by an aneurysm clip with a closing force of 24 g. Mice were treated intravesically with adelmidrol + sodium hyaluronate daily for 48 h and 7 days after SCI. Adelmidrol + sodium hyaluronate reduced significantly mast cell degranulation and down-regulated the nuclear factor-κB pathway in the bladder after SCI both at 48 h and 7days. Moreover, adelmidrol + sodium hyaluronate reduced nerve growth factor expression, suggesting an association between neurotrophins and bladder pressure. At 7 days after SCI, the bladder was characterized by a marked bacterial infection and proteinuria; surprisingly, adelmidrol + sodium hyaluronate reduced significantly both parameters. These data show the protective roles of adelmidrol + sodium hyaluronate on bladder following SCI, highlighting a potential therapeutic target for the reduction of bladder changes.

ASIC3 fine-tunes bladder sensory signaling.

Acid-sensing ion channels (ASICs) are trimeric proton-activated, cation-selective neuronal channels that are considered to play important roles in mechanosensation and nociception. Here we investigated the role of ASIC3, a subunit primarily expressed in sensory neurons, in bladder sensory signaling and function. We found that extracellular acidification evokes a transient increase in current, consistent with the kinetics of activation and desensitization of ASICs, in ~25% of the bladder sensory neurons harvested from both wild-type (WT) and ASIC3 knockout (KO) mice. The absence of ASIC3 increased the magnitude of the peak evoked by extracellular acidification and reduced the rate of decay of the ASIC-like currents. These findings suggest that ASICs are assembled as heteromers and that the absence of ASIC3 alters the composition of these channels in bladder sensory neurons. Consistent with the notion that ASIC3 serves as a proton sensor, 59% of the bladder sensory neurons harvested from WT, but none from ASIC3 KO mice, fired action potentials in response to extracellular acidification. Studies of bladder function revealed that ASIC3 deletion reduces voiding volume and the pressure required to trigger micturition. In summary, our findings indicate that ASIC3 plays a role in the control of bladder function by modulating the response of afferents to filling.

A kit ligand, stem cell factor as a possible mediator inducing overactive bladder.

To investigate whether c-kit ligand, stem cell factor (SCF) affects the biological behavior of overactive bladder (OAB) and discuss the role of SCF as a possible mediator inducing OAB. First, we performed an immunohistochemical study to examine the localization of SCF in the guinea pig and human bladder. Next, urinary SCF levels were measured in patients with OAB and in control subjects to evaluate a potential biomarker for the diagnosis of OAB. Third, we examined the effect of SCF administration on the urinary bladder using guinea pigs to obtain additional information about SCF. The animals were administered with mouse SCF, and cystometry was performed. The following urodynamic parameters were analyzed: inter-contraction interval, maximum voiding pressure, pressure threshold, detrusor baseline pressure, and the number of non-voiding contractions. Immunohistochemical study showed that the expression of SCF was observed throughout the bladder wall, but especially in the urothelium of guinea pig and human bladder. Medians and IQRs of urinary SCF and SCF/creatinine levels in OAB patients (85.9 pg/mL [42.8, 199.0] and 1.30 [0.56, 2.71], respectively) were significantly higher than in control subjects (18.9 pg/mL [5.0, 43.6] and 0.26 [0.13, 0.43], respectively). SCF administration dose-dependently shortened the intercontraction interval and an increased number of non-voiding contractions (P < 0.05). Our present data suggest that SCF produced in the urinary bladder may act as a possible mediator by binding to c-kit, which is expressed in ICC-like cells in the suburothelial and muscle layers, to control bladder function.

MP31-07 URINARY STEM CELL FACTOR MAY BECOME THE DIAGNOSABLE BIOMARKER OF OVERACTIVE BLADDER IN WOMEN

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Non-neurogenic Voiding Dysfunction I1 Apr 2017MP31-07 URINARY STEM CELL FACTOR MAY BECOME THE DIAGNOSABLE BIOMARKER OF OVERACTIVE BLADDER IN WOMEN Takashi Hamakawa, Yasue Kubota, Yuya Ota, Naoko Unno, Rika Banno, Masa Takada, Shoichi Sasaki, Kenjiro Kohri, and Takahiro Yasui Takashi HamakawaTakashi Hamakawa More articles by this author , Yasue KubotaYasue Kubota More articles by this author , Yuya OtaYuya Ota More articles by this author , Naoko UnnoNaoko Unno More articles by this author , Rika BannoRika Banno More articles by this author , Masa TakadaMasa Takada More articles by this author , Shoichi SasakiShoichi Sasaki More articles by this author , Kenjiro KohriKenjiro Kohri More articles by this author , and Takahiro YasuiTakahiro Yasui More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.961AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES C-kit, as known a receptor tyrosine kinase protein and a receptor of stem cell factor (SCF), not only acts as a marker of interstitial cells of Cajal, but also plays a significant role in the control of bladder spontaneous activity. And it could be an interesting target for the clinical treatment of overactive bladder (OAB). Although SCF binding to c-kit is associated with various biologic phases, the distribution and role of SCF in the urinary bladder remain unknown. Thus, we speculated that c-kit and its ligand SCF could play an important role in the control of bladder function. The objective of this study was to investigate whether SCF affects the biological behaviour of OAB. METHODS Differentiation between OAB and control was based on symptoms and a questionnaire of Overactive Bladder Symptom Score (OABSS). Urinary SCF levels were measured in patients with OAB and in control subjects by enzyme-linked immunosorbent assay (ELISA). The urinary SCF levels were compared among controls and OAB groups, and also between OAB patients ?75 years and <75 years. RESULTS A total of 93 women with OAB and 71 controls were enrolled. The mean age was 74.1± 13.0 years for the OAB groups and 67.1± 15.6 years for the control group. The average urinary SCF/creatinine levels in OAB patients was 1.589 ± 2.837, and in the control group was 0.558 ± 0.773 (p<0.001) (Fig.1). Analysis of urinary SCF/Cr levels among OAB group and controls by age showed no significant differences. CONCLUSIONS Urinary SCF levels were significantly higher in women with OAB. The urinary SCF level was not associated with ageing in OAB patients and controls. These results suggested that the SCF/C-kit pathway has a potential of contribution to the onset of OAB, and urinary stem cell factor might become the evaluable biomarker of OAB in women, objectively. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e401 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Takashi Hamakawa More articles by this author Yasue Kubota More articles by this author Yuya Ota More articles by this author Naoko Unno More articles by this author Rika Banno More articles by this author Masa Takada More articles by this author Shoichi Sasaki More articles by this author Kenjiro Kohri More articles by this author Takahiro Yasui More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Characterization of miRNA-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunction.

Bladder outlet obstruction (BOO) induces significant organ remodeling, leading to lower urinary tract symptoms accompanied by urodynamic changes in bladder function. Here, we report mRNA and miRNA transcriptome sequencing of bladder samples from human patients with different urodynamically defined states of BOO. Patients' miRNA and mRNA expression profiles correlated with urodynamic findings. Validation of RNA sequencing results in an independent patient cohort identified combinations of 3 mRNAs (NRXN3, BMP7, UPK1A) and 3 miRNAs (miR-103a-3p, miR-10a-5p, miR-199a-3p) sufficient to discriminate between bladder functional states. All BOO patients shared cytokine and immune response pathways, TGF-β and NO signaling pathways, and hypertrophic PI3K/AKT signaling pathways. AP-1 and NFkB were dominant transcription factors, and TNF-α was the top upstream regulator. Integrated miRNA-mRNA expression analysis identified pathways and molecules targeted by differentially expressed miRNAs. Molecular changes in BOO suggest an increasing involvement of miRNAs in the control of bladder function from the overactive to underactive/acontractile states.

(398) Fully-implantable, wireless technology for optogenetic control of bladder sensory neurons

Bladder pain and dysfunction are sources of profound debilitation for millions of people in the United States with interstitial cystitis/bladder pain syndrome, overactive bladder, and neurogenic bladder. Current treatments for these disorders are often ineffective and do not address the underlying pathology. A substantial barrier to the development of improved therapeutics is insufficient access to peripheral mechanisms by which the bladder can be controlled. Our preliminary efforts have aimed at developing a suite of technologies that use a combination of peripherally-implanted, wireless optoelectronic systems for monitoring and control of bladder activity. Our hardware and interfaces use soft, fully-implantable microscale devices with advanced design features specifically configured for essentially permanent interfacing with the pelvic nerve. This technology has provided unique access to bladder functionality, thus enabling novel insight into the mechanisms of bladder control and pain. We have shown using this new technology the ability to wirelessly electrically stimulate and record bladder function through pelvic nerve activity. Additionally, we have shown the ability control bladder function through the viral delivery of excitatory and inhibitory optogenetic channels. This work was supported in part by a grant from GSK (GlaxoSmithKline).