Mechanisms/Treatments of Lower Urinary Tract Dysfunction After Spinal Cord Injury

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INTRODUCTION ¿ The goals of this program are to characterize lower urinary tract (LUT) dysfunction due to spinal cord injury and to test new therapies. Effects of spinal! cord injury are multifaceted involving changes in the spinal cord, peripheral neurons and different cell types in the bladder and urethra leading to detrusorsphincter- dyssynergia, urothelial cell hyperplasia, interstitial cell pacemaker activity, afferent nerve sensitization and smooth muscle cell hypertrophy. Therapies to be tested include botulinum neurotoxin serotype A, |33-adrenergic receptor agonists, PDE-5 inhibitrors, and nerve growth factor and brain-derived neurotrophic factor antibodies. Optical mapping techniques we developed are extremely effective in studying LUT and are a key link between projects. These approaches utilize unique mouse and rat preparations including spinal cord slices, bladder-urethra sheets, sheets with spinal nerves, wall cross-sections and 'inline' primary urothelial, neuronal, interstitial and smooth muscle cells. GCaMP4 encoded viral vectors will be used to label sensory nerves innervating the bladder and sensory nerves and motoneurons in the spinal cord controlling the bladder and urethral sphincter. The program Pis and core Directors have extensive expertise in urologic research and optical mapping. Anthony Kanai, project 1 and imaging core co-director, is an expert in afferent nerve, urothelial and interstitial cell interactions and was first to use optical mapping to study the LUT. Lori Birder, project 2, is an expert in urothelial cell pathophysiology and was first to demonstrate their neuronal-like properties. Naoki Yoshimura, project 3, is an expert in the pathophysiology of sensory neurons and was first to demonstrate changes in ion channel expression in DRG neurons as a mechanism for bladder afferent sensitization. William de Groat, project 4 and animal core director, is an expert on the autonomic pathophysiology of the LUT and was first to show the role of C-fiber afferents in bladder overactivity. Guy Salama, imaging core co-director, is an expert in optical mapping and was first to develop methods to simultaneously record action potentials and Ca2+ transients. We are confident that our experience and unique approaches will lead to a very interactive and fruitful program.