Neurotrophic factors such as nerve growth factor (NGF) play a critical role in directing the growth and survival of nerves supplying the bladder. NGF has been implicated in the morphological and functional alterations in neural pathways following obstruction or denervation of the adult urinary bladder. In contrast, the role of NGF and other neurotrophic factors has not been studied during fetal and neonatal development of bladder innervation despite the prevalence of micturition disorders associated with posterior urethral valves (PUV), myelomeningocele, and Prune Belly Syndrome. The proposed experiments will test the hypotheses that trophic interactions occur between smooth muscle cells in the growing bladder and their sympathetic and parasympathetic innervation. The strategy for testing this hypothesis will rely on smooth muscle extracts of supernatants from tissue cultures derived from bladders of rats at different stages of development (F18, N01, N02, N05, N10, N15, N30) which will be bioassayed for neurotrophic factors. The effect of bladder extracts on the survival, growth and transmitter phenotype of cultured neurons from dorsal root (afferent) and major pelvic (efferent) ganglia will be assessed. Since sensory neurons depend on NGF for growth and transmitter phenotype, and because maturation of afferents may be responsible for changes in micturition reflexes in neonates, NGF synthesis, release and receptor expression in the developing bladder will be studied. The time course for neurotrophic factor production will be compared to bladder growth as measured by weight, DNA, protein content, and thymidine uptake. To ascertain what environmental factors influence NGF production and myocyte growth, activation and blockade of adrenergic, cholinergic, and peptidergic receptors in cultures of bladder and myocytes will be performed. Target organ-nerve interactions are most dynamic during development; therefore obstruction of the fetal or neonatal bladder can be expected to produce dramatic alterations in neural pathways, causing severe abnormalities in micturition. Indeed, obstruction of the bladder in newborn animals and humans is often devastating with regard to bladder and renal function. Obstructive problems including PUV and myelomeningocele are commonly encountered by pediatric urologists. Insight into mechanisms directing the neural control of the growing bladder is crucial for understanding abnormalities of micturition in the newborn and may shed light on bladder dysfunction which occurs throughout adulthood in response to bladder hypertrophy.
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