Functional and Molecular Mechanisms Underlying Detrusor-Sphincter Dyssynergia (DSD) in SCI
Abstract
Neurogenic lower urinary tract dysfunction associated detrusor overactivity (DO) during urine storage and detrusor-sphincter dyssynergia (DSD) (i.e., concomitant contractions of detrusor and external urethral sphincter [EUS]) during voiding in people with spinal cord injury (SCI) is a great risk factor of urological problems such as urinary incontinence, retention, urinary tract infection, upper urinary tract deterioration, and autonomic dysreflexia. Several treatments including pharmacotherapies are available, but often with limited efficacy and bothersome side effects, and a significant number of SCI patients rely on intermittent catheterization for bladder emptying. Also, the mechanisms inducing DO after SCI such as nerve growth factor (NGF)-dependent increased excitability of C-fiber afferent pathways and upregulation of nociceptive receptors (e.g., TRPV1, P2X2/3) expressed on afferent nerves have been studied; however, those underlying DSD are not well clarified. Therefore, this proposal will seek to identify the functional and molecular mechanisms of voiding dysfunction and DSD, especially focusing on the involvement of brain-derived neurotrophic factor (BDNF). Using adult female mice with chronic SCI induced by Th8/9 spinal cord transection, we will investigate: (1) the time-dependent changes in bladder and external urethral sphincter (EUS) activity to evaluate the progression of DSD and inefficient voiding as well as alterations in expression of mechanosensitive channels such as ASICs, ENaC, or Piezo in bladder afferent pathways after SCI (Aim 1) and (2) the effects of BDNF antibody treatment on SCI-induced DSD/inefficient voiding and upregulated mechanosensitive channel expression in afferent pathways (Aim 2). If successfully completed, this study is likely to identify the mechanisms inducing voiding dysfunction in SCI and new therapeutic targets in growth factors and/or mechanosensitive channels for the treatment of SCI-induced voiding dysfunction. Thus, it is expected that this project, upon completion, will provide the foundation for future clinical translation of anti-BDNF therapy in military Service members, their family members, and/or the U.S. Veteran population who suffer from neurogenic lower urinary tract dysfunction after SCI. The anti-BDNF therapy could also be extended to a general population of people with SCI or other spinal cord lesions such as multiple sclerosis. The long-term objectives of the research program are to establish new and effective therapeutic targets and/or interventions strategies for the treatment of lower urinary tract complications of SCI.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710403
Entities
People
- Naoki Yoshimura
Organizations
- United States Army
- University of Pittsburgh