DIABETIC BLADDER AFFERENT NEURON AND NGF GENE THERAPY

描述(改编自申请者摘要)：超过一半的糖尿病患者 糖尿病患者在病程中会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？传入性神经病一直很好 证明在糖尿病膀胱病变中起关键作用，这是一个后果 对DM。感觉神经元在膀胱内和整个膀胱的功能 身体是通过调节细胞神经肽的合成来控制的， 神经生长因子等信号对离子通道表达的影响 (NGF)。糖尿病患者NGF水平降低，进而导致研究 神经生长因子的替代物。外源性NGF应用和NGF基因治疗 显示可以预防糖尿病的行为和生化表现 动物的感觉神经病。然而，潜在的功能机制 导致糖尿病膀胱病的感觉通路的改变并没有 已被阐明。研究人员假设：1)膀胱传入 糖尿病患者神经元兴奋性降低，2)NGF工程复制 单纯疱疹病毒(HSV)缺陷型和局部注射NGF可预防 逆转糖尿病引起的膀胱传入神经元的改变，从而 改善膀胱功能。这笔赠款的科学目标是：1) 识别和描述糖尿病患者的细胞变化 膀胱。糖尿病膀胱传入神经元兴奋性的研究将使用 膜片钳记录技术在链脲佐菌素诱导的糖尿病大鼠中的应用 与对照组和喂食蔗糖的利尿剂动物相比。2)开发小说 治疗糖尿病膀胱病的分子治疗策略。神经生长因子基因治疗 在糖尿病膀胱中的作用将被研究。复制缺陷型单纯疱疹病毒载体 携带NGF基因的人将被注射到膀胱壁，或者NGF将被 通过渗透泵局部注入膀胱壁。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， 用NGF基因治疗逆转，甚至治愈糖尿病膀胱病变。这 在糖尿病患者的泌尿外科护理中代表着高度优先的地位。

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.