DIABETIC BLADDER AFFERENT NEURON AND NGF GENE THERAPY

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DESCRIPTION (Adapted from the Applicant's Abstract): More than half of diabetic patients are affected by voiding dysfunction during the course of diabetes mellitus (DM) but why does this happen? Afferent neuropathy has been well documented to play a crucial role in diabetic cystopathy that is a consequence of DM. The function of sensory neurons within the bladder and throughout the body is controlled by modulating cellular synthesis of neuropeptides and the expression of ion channels in response to signals such as nerve growth factor (NGF). The level of NGF is decreased in DM that in turn leads to investigation of NGF replacement. Exogenous NGF administration and NGF gene therapy has been shown to prevent the behavioral and biochemical manifestations of diabetic sensory neuropathy in animals. However, the mechanism underlying functional alternation in sensory pathways responsible for diabetic cystopathy has not been elucidated. The investigators hypothesize that: 1) the bladder afferent neuron excitability is decreased in diabetes, and 2) NGF engineered replication defective herpes simplex virus (HSV) and regional infusion of NGF can prevent and reverse the diabetes-induced change in bladder afferent neuron and thereby improve bladder function. The scientific objectives of this grant are to: 1) Identify and characterize the cellular changes which occur in the diabetic bladder. Diabetic bladder afferent neuron excitability will be studied using patch-clamp recording techniques in streptozotocin induced diabetic rats and compared with control and sucrose-fed diuretic animals. 2) Develop novel molecular therapeutic strategies to treat diabetic cystopathy. NGF gene therapy in the diabetic bladder will be studied. Replication defective HSVvectors carrying the NGF gene will be injected into the bladder wall or NGF will be topically instilled into the bladder wall via an osmotic pump. By defining bladder afferent neuropathy of DM, one can offer the hope of prevention, reversal, and even cure of diabetic cystopathy with NGF gene therapy. This represents a high priority in the urologic care of diabetic patients.