Pannexin 1 channels, new players in diabetic bladder dysfunction

Pannexin 1 通道，糖尿病膀胱功能障碍的新参与者

• 批准号: 9803135
• 负责人: SYLVIA OTTILIE SUADICANI
• 金额: $ 48.23万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-03 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9803135
• 关键词: Address; Affect; Animal Model; Area; Automobile Driving; Biochemical; Bladder; Bladder Dysfunction; Bladder Urothelium; Cell Culture Techniques; Cells; Cellular Mechanotransduction; Chemicals; Complex; Complication; Development; Diabetes Mellitus; Diabetic mouse; Disease; Diuresis; Down-Regulation; Environment; Functional disorder; Glucose; Harvest; Histologic; Hyperglycemia; Hypoxia; Impairment; In Vitro; Individual; Inflammasome; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Intervention; Knockout Mice; Knowledge; Lead; Mediator of activation protein; Methods; Modeling; Molecular; Motor; Multiple Sclerosis; Mus; Natural regeneration; Neurogenic Bladder; Organ; Overactive Bladder; Paper; Pathology; Patients; Periodicity; Pharmacology; Pharmacotherapy; Physiology; Play; Polyuria; Role; Sensory; Signal Transduction; Stains; Streptozocin; Stress; System; Testing; Time; Up-Regulation; Urothelial Cell; advanced disease; combinatorial; diabetes management; diabetic; extracellular; genetic manipulation; improved; insight; novel; novel strategies; prevent; receptor; response; therapeutic target; transmission process; urologic

Abstract In type 1 diabetes mellitus (T1DM), the bladder undergoes a progressive transition from a normal to an overactive and then to an underactive state that occurs along the course of the disease. The factors and mechanisms that drive these temporal changes in bladder function are still not completely understood. Moreover, while an overactive diabetic bladder can be managed by pharmacotherapy, the current pharmacological interventions have limited effects on a decompensated, underactive diabetic bladder. There is thus a clear need to advance our knowledge in this area and to identify novel molecular mediators in diabetic bladder dysfunction (DBD) that can be targeted to develop strategies to prevent bladder decompensation and to better manage an underactive diabetic bladder. In this R01 application we address this gap in our knowledge and approach DBD from a new perspective, moving from the traditional focus on neurogenic and myogenic mechanism in DBD pathology to investigate the effects of diabetes on the bladder urothelium. In this context, we advance the proposal that urothelial pannexin 1 (Panx1) channels are novel players in mechanisms of DBD. This proposal is supported by our preliminary studies with streptozotocin (STZ) diabetic mice that diabetes causes an early upregulation of Panx1 that is then followed by downregulation at later stages of the disease. Notably, these temporal changes in Panx1 expression coincided with the emergence of DBD and with the transition of the bladder to decompensated underactive state. We have shown that Panx1 channels play essential roles in the urothelial mechanosensory, transduction and signaling (UMTS) system. Changes in Panx1 expression can thus alter the bladder sensitivity, and the sensory and motor responses to bladder distention. In this regard, it is possible that an early upregulation of Panx1 and thereby of the UMTS system could lead to the increased bladder activity observed at early stages of diabetes. As the disease advances, a subsequent and progressive downregulation of Panx1 and thereby of the UMTS system would then bring the bladder from a compensated to a decompensated state. The studies that we proposed in this application will test this hypothesis that dysregulation of urothelial Panx1 expression is one of the main factors leading to changes in bladder function and driving its transition from an overactive compensated to underactive decompensated state. These studies are expected to not only demonstrate that urothelial Panx1 channels are novel players in DBD, but will also provide insights as to whether strategies aimed at restoring Panx1 expression in the diabetic bladder may provide a novel approach to treat DBD and prevent bladder decompensation.

摘要 在1型糖尿病(T1 DM)中，膀胱经历了从正常到正常的渐进性转变 过度活跃，然后进入在疾病过程中出现的活动不足的状态。这些因素和 驱动膀胱功能的这些时间变化的机制仍然不完全清楚。此外， 虽然过度活跃的糖尿病膀胱可以通过药物治疗来管理，但目前的药物治疗 干预措施对失代偿、活动不足的糖尿病膀胱的效果有限。因此，显然有必要 促进我们在这一领域的认识，并寻找糖尿病膀胱功能障碍的新分子介质 (DBD)可以有针对性地制定预防膀胱失代偿和更好地管理 糖尿病患者的膀胱活动不足。 在此R01应用程序中，我们解决了我们知识中的这一差距，并从新的角度处理DBD， 从传统上对DBD病理学中神经源性和肌源性机制的关注转向研究DBD的 糖尿病对膀胱尿路上皮的影响。在这种情况下，我们提出了尿路上皮膜联蛋白的建议 1(Panx1)通道是DBD发病机制中的新成员。这项建议得到了我们初步的支持 对链脲佐菌素(STZ)糖尿病小鼠的研究表明，糖尿病导致Panx1的早期上调，然后 随后在疾病的后期阶段下调调控。值得注意的是，Panx1表达的这些时间变化 与DBD的出现和膀胱向失代偿低活动状态的转变相吻合。 我们已经证明，Panx1通道在尿路上皮细胞的机械感觉、转导中起重要作用。 和信令(UMTS)系统。因此，Panx1表达的变化可以改变膀胱的敏感性，而 对膀胱扩张的感觉和运动反应。在这方面，提早上调 Panx1和因此的UMTS系统可以导致在早期观察到的膀胱活动增加 糖尿病。随着疾病的进展，Panx1随后逐渐下调，从而导致 UMTS系统随后会将膀胱从代偿状态带到失代偿状态。 我们在本申请中提出的研究将检验这一假设，即 尿路上皮Panx1的表达是导致膀胱功能和驱动力改变的主要因素之一 它从过度活跃的补偿状态过渡到欠活跃的失代偿状态。这些研究是 预计不仅将证明尿路上皮Panx1通道是DBD的新参与者，而且还将提供 关于旨在恢复糖尿病膀胱中Panx1表达的策略是否可能提供 治疗DBD和预防膀胱失代偿的新方法。