Diabetic Urethral Pathophysiology and Afferent Therapy

糖尿病尿道病理生理学和传入治疗

• 批准号: 6460437
• 负责人: MATTHEW O FRASER
• 金额: $ 26.24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6460437
• 关键词: diabetes mellitus; diabetes mellitus therapy; electromyography; electrophysiology; gene therapy; immunofluorescence technique; laboratory rat; neurotransmitters; perfusion; streptozotocin; urethra; urethra disorder; urinary bladder; urology; vascular smooth muscle; voltage /patch clamp

DESCRIPTION (provided by applicant): Diabetes mellitus (DM) is a severe systemic condition that causes serious damage to the lower urinary tract. Diabetic cystopathy is well established, but little is known of DM effects urethral function. Utilizing techniques developed in our laboratory, we propose to mount a systematic in vivo physiological and pharmacological analysis of urethral function in DM animals. Additionally, we propose the first-ever biomechanical analysis of the normal and DM urethra, utilizing techniques developed for vascular biomechanical studies. Complementary in vitro urethral strip studies will also be performed. Finally, we will explore the use of afferent gene therapy to combat the urethral dysfunction caused by DM. We hypothesize: 1) DM results in a functional outlet obstruction caused by incomplete urethral relaxation; 2) DM changes the biomechanical properties of the urethra, contributing to outlet dysfunction; 3) DM results in a disruption of urethral afferent function, thereby contributing to detrusor hypomotility; and 4) Urethral NGF gene therapy can improve urethral innervation in diabetic animals. The Scientific Objectives of this grant are to: 1. Characterize alterations in the physiological and biomechanical properties of the urethra that occur in diabetes using: a) combined isolated cystometry and anterograde urethral perfusion pressure measurements, b) leak point pressure measurements using the vertical tilt table and intravesical pressure clamp, c) whole urethra biomechanical studies, and d) in vitro urethral strip electrical field stimulation studies. 2. Investigate urethral afferent neuropathy in diabetic cystopathy directly by in vivo physiological techniques and in vitro electrophysiological recording of identified urethral afferent neurons, and indirectly by neuroanatomical techniques: a) the effect of intraurethral delivery of irritants on bladder activity will be assessed, b) the phenotypic properties of identified urethral afferent neurons will be determined using patch clamp techniques, and c) immunofluorescent assessment of urethral afferent innervation. 3. Study the novel and exciting potential of gene therapy in the diabetic urethra using a replication-defective, latency-promoter HSV- 1 vector carrying the NGF gene. By defining the urethral pathology of DM, we can offer the hope of prevention, reversal, and even cure of diabetic urologic dysfunction. This is a high priority in the urologic care of diabetic patients.

描述（由申请人提供）：糖尿病（DM）是一种严重的 导致下尿路严重损伤的全身性疾病。 糖尿病膀胱病是公认的，但很少有人知道糖尿病的影响 尿道功能利用我们实验室开发的技术，我们建议 进行系统的体内生理学和药理学分析， DM动物的尿道功能。此外，我们还首次提出 正常和糖尿病尿道的生物力学分析，利用技术 用于血管生物力学研究。体外辅助尿道 还将进行剥离研究。最后，我们将探讨如何使用 传入基因治疗，以对抗糖尿病引起的尿道功能障碍。 我们假设：1）DM导致功能性出口梗阻， 不完全尿道松弛; 2）DM改变生物力学特性， 尿道，导致出口功能障碍; 3）DM导致破裂 尿道的传入功能，从而有助于逼尿肌运动不足; 尿道神经生长因子基因治疗可改善糖尿病患者的尿道神经支配 动物 该补助金的科学目标是：1。描述变化的特征 尿道的生理和生物力学特性， 糖尿病使用：a）结合单独膀胱测压和顺行尿道 灌注压力测量，B）使用 垂直倾斜台和膀胱内压力钳，c）整个尿道 生物力学研究，以及d）体外尿道条电场 刺激研究。2.糖尿病患者尿道传入神经病变的研究 直接通过体内生理技术和体外 鉴定的尿道传入神经元的电生理记录，和 间接通过神经解剖技术：a）尿道内的影响 将评估刺激物的递送对膀胱活性的影响，B）表型 所鉴定的尿道传入神经元的性质将使用 膜片钳技术，和c）尿道的免疫荧光评估 传入神经支配3.研究基因治疗的新颖和令人兴奋的潜力 在糖尿病尿道中使用复制缺陷型潜伏期促进剂HSV- 1 携带NGF基因的载体。 通过明确糖尿病的尿道病理，我们可以提供预防的希望， 逆转，甚至治愈糖尿病泌尿功能障碍。这是一个高 糖尿病患者的泌尿外科护理优先。