Mechanisms of Neurogenic Bladder Dysfunction in EAE Mice

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DESCRIPTION (provided by applicant): Neurogenic Urinary Incontinence (NUI) is the most bothersome manifestation of Neurogenic Bladder Dysfunction (NBD). NBD refers collectively to bladder dysfunctions that are caused by neurological problems such as multiple sclerosis (MS). MS is the most common disabling neurological disorder affecting women between 20 and 45 years old. MS is a progressive degenerative autoimmune disease that impairs neuronal functions due to demyelinating lesions throughout the nervous system, affecting the function of the bladder and its outlet. MS is twice as frequent in women as in men, and more than 80% of women with MS present with NUI. The prevalence of NUI rises to more than 96% in those with the disease for longer than 10 years. While the underlying pathophysiology of MS-associated NBD and NUI remains poorly understood, it is suggested that NBD occurs as a result of demyelination interrupting the neural pathways connecting the central nervous system control to the spinal and peripheral neuronal pathways of the bladder and lower urinary tract function, thus disrupting both the storage and voiding phase of bladder function. Thus, NUI can present as a result of failure of bladder storage (urge incontinence) or emptying (overflow incontinence). Further, the fluctuating nature of MS with unpredictable patterns of remissions and relapses exposes women with MS to deteriorating bladder function that contributes to the heavy burden of morbidity and mortality associated with MS. We have recently created a mouse model of NBD that mimics the clinical course of MS in humans, including storage dysfunction, voiding problems and detrusor sphincter dyssynergia (DSD). The mouse with Experimental Autoimmune Encephalomyelitis (EAE) has afforded us with the unique opportunity to investigate the key unanswered research questions related to NBD and NUI. We hypothesize that female SWXJ mice with EAE in clinical scores 0-4 demonstrate a corresponding storage or voiding bladder dysfunction predictive of the type of NBD. Further, we hypothesize that mice with bladder outlet obstructive pattern from DSD have overflow incontinence due to areflexia bladder, and mice without DSD have overactive bladder (OAB) and urge incontinence due to hyperreflexia bladder. The hypotheses will be tested with three specific aims. In aim 1 the temporal characteristics of storage and voiding phases of NBD in EAE will be assessed by simultaneous cystometrogram and electromyogram. Aim 2 will correlate CNS histopathology and neurologic deficit with defined storage and voiding phases of NBD in EAE mice. Finally, aim 3 will examine contractile responses of the whole neurogenic bladder in vitro. This animal model combined with innovative methods of simultaneous assessment of bladder and outlet function, will allow us to investigate the mechanisms of NUI in a whole new way, opening the gates for discovery of preventive and therapeutic interventions for millions of women suffering from NUI. PUBLIC HEALTH RELEVANCE: Neurogenic Urinary Incontinence (NUI) is the most bothersome manifestation of Neurogenic Bladder Dysfunction (NBD). NBD refers collectively to bladder dysfunctions that are caused by neurological problems such as multiple sclerosis (MS). The bladder has two primary functions urine storage and emptying. In NUI either of these functions might be impaired. Using a mouse model of MS, we will investigate the specific mechanism of NUI leading to rational design of preventive and therapeutic interventions.