DIABETIC BLADDER AFFERENT NEURON AND NGF GENE THERAPY

描述（改编自申请人摘要）：超过一半的糖尿病患者 患者在糖尿病过程中受到排尿功能障碍的影响 糖尿病（DM），但为什么会发生这种情况？传入神经病变一直很好 据记载，在糖尿病膀胱病变中起着至关重要的作用， 的DM。感觉神经元在膀胱内和整个膀胱的功能 身体是通过调节神经肽的细胞合成来控制的， 离子通道响应信号如神经生长因子的表达 （NGF）。糖尿病患者的神经生长因子水平降低，这反过来又导致了研究 NGF替代品外源性NGF给药和NGF基因治疗已被广泛应用于临床。 显示可以预防糖尿病患者的行为和生化表现 动物的感觉神经病然而，功能性的潜在机制 糖尿病性膀胱病感觉通路的改变 被阐明。研究人员假设：1）膀胱传入神经 神经元兴奋性在糖尿病中降低，和2）NGF工程复制 缺陷型单纯疱疹病毒（HSV）和局部输注神经生长因子可以预防 逆转糖尿病引起的膀胱传入神经元的变化， 改善膀胱功能。该补助金的科学目标是：1） 识别和表征糖尿病患者中发生的细胞变化 膀胱糖尿病膀胱传入神经元兴奋性将使用 膜片钳技术在链脲佐菌素诱导的糖尿病大鼠和 与对照组和蔗糖喂养的利尿动物相比。2)开发新型 分子治疗策略治疗糖尿病膀胱病。神经生长因子基因治疗 糖尿病患者的膀胱将被研究。复制缺陷型HSV载体 携带神经生长因子基因将被注射到膀胱壁或神经生长因子将 通过渗透泵局部滴入膀胱壁。通过定义 糖尿病的膀胱传入神经病变，可以提供预防的希望， 逆转甚至治愈糖尿病膀胱病变。这 在糖尿病患者的泌尿科护理中具有高度优先权。

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.