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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

基本信息

批准号：
10078231
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
项目类别：
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/10078231
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 Urothelium advanced disease combinatorial diabetes management diabetic extracellular genetic manipulation improved insight novel novel strategies prevent receptor response therapeutic target transmission process urologic

项目摘要

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