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Role of Pannexins in Urinary Bladder Pathology

Pannexins 在膀胱病理学中的作用

基本信息

批准号：
9116192
负责人：
JONATHAN M BECKEL
金额：
$ 12.01万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9116192
关键词：
Acrolein Agonist American Animal Model Animals Apoptosis Bacterial Model Binding Bladder Bladder Control Bladder Diseases Bladder Tissue Cell physiology Cells Chemical Stimulation Chemicals Cultured Cells Cyclophosphamide Cystitis Cytosol Development Disease Economic Burden Enzyme-Linked Immunosorbent Assay Epithelial Cells Epithelium Esthesia Etiology Event Frequencies Gene Expression Genetic Health Health Care Costs Immunoblotting Inflammation Inflammatory Injection of therapeutic agent Interleukin-1 beta Interleukin-18 Interstitial Cystitis Intravesical Administration Ions Light Limb structure Link Lipopolysaccharides Maintenance Measurement Measures Mechanical Stimulation Mechanics Mediating Membrane Potentials Neurons Nicotinic Receptors Overactive Bladder Pain Pathology Pathway interactions Patients Pelvis Permeability Phosphorylation Play Post-Translational Protein Processing Potassium Production Public Health Purinoceptor Rattus Reflex action Research Role Sensory Signal Pathway Signal Transduction Stimulus Stretching Surface Techniques Tight Junctions Tissues Urination Urothelial Cell Urothelium afferent nerve cell type cellular targeting channel blockers cost cytokine design effective therapy extracellular genetic approach patch clamp receptor research study response simulation small molecule stem urinary urinary bladder epithelium

项目摘要

DESCRIPTION (provided by applicant): We have recently determined that ATP can be released from the urinary bladder epithelium (urothelium) in response to stretch and chemical stimulation through pannexin channels. As purinergic signaling is thought to play a critical role i the development of bladder pathology, pannexin channels may be an important target in the treatment of disorders of the urinary bladder such as interstitial cystitis/painful bladder syndrom (IC/PBS). Therefore our proposed research aims to further examine the role of pannexin channels in purinergic signaling in the urothelium. In our first aim, we propose to examine the pathways responsible for the activation or inactivation of the pannexin channel itself, such as nitrosylation or phosphorylation. While previous studies have elucidated a wide variety of stimuli responsible for causing ATP release, no studies to date have examined the pathways that connect urothelial cell stimulation to pannexin channel opening. Therefore we will attempt to determine the pathways involved in activating/deactivating pannexin channels in the urothelium. As we have previously demonstrated that simulation of urothelial cells with a3 or a7 nicotinic receptor agonists can activate or inhibit ATP release respectively, we will use these compounds in cultured rat urothelial cells as our experimental stimuli. It is our hope that these experiments will greatly increase our understanding of the mechanisms linking urothelial stimulation to ATP release. As ATP has been strongly implicated in a number of pathological bladder disorders, such as overactive bladder, we believe that this research has the potential to elucidate new targets for the treatment of bladder pathology. Because pannexin channels have been found to be important for the activation of the inflammasome in a wide variety of tissues, and inflammation is an important part of bladder pathology, the second half of our proposed study will examine how pannexin channels are important to the induction or maintenance of inflammation in the urinary bladder. To examine this question, we propose to induce bladder inflammation by injection of either bacterial lipopolysaccharides or cyclophosphamide and study the signaling pathways that connect pannexin-mediated ATP release to the increased frequency of urination observed in bladder pathology. These signaling pathways include activation of purinergic receptors on the surface of urothelial cells, the oligomerization of NLRP3/NLRC4 inflammasomes, and the activation of events downstream of IL-1ß receptor stimulation, such as increased paracellular permeability. It is our hope that the experiments in this aim will elucidate a new target for pharmacological or genetic treatment of pathological bladder disorders involving inflammation, such as interstitial cystitis.

描述（由申请人提供）：我们最近确定，ATP 可以通过 pannexin 通道响应拉伸和化学刺激而从膀胱上皮（尿路上皮）释放。由于嘌呤能信号被认为在膀胱病理学的发展中发挥着关键作用，因此潘联蛋白通道可能是治疗间质性膀胱炎/膀胱疼痛综合征（IC/PBS）等膀胱疾病的重要靶点。因此，我们提出的研究旨在进一步研究泛联蛋白通道在尿路上皮嘌呤能信号传导中的作用。在我们的第一个目标中，我们建议检查负责潘联蛋白通道本身激活或失活的途径，例如亚硝基化或磷酸化。虽然之前的研究已经阐明了导致 ATP 释放的多种刺激，但迄今为止还没有研究检查将尿路上皮细胞刺激与 pannexin 通道开放联系起来的途径。因此，我们将尝试确定参与激活/失活尿路上皮泛联蛋白通道的途径。正如我们之前所证明的，用a3或a7烟碱受体激动剂模拟尿路上皮细胞可以分别激活或抑制ATP释放，我们将在培养的大鼠尿路上皮细胞中使用这些化合物作为我们的实验刺激物。我们希望这些实验将大大增加我们对尿路上皮刺激与 ATP 释放之间的联系机制的理解。由于 ATP 与许多膀胱病理性疾病（例如膀胱过度活动症）密切相关，我们相信这项研究有可能阐明膀胱病理治疗的新靶点。由于已发现pannexin通道对于多种组织中炎症小体的激活非常重要，并且炎症是膀胱病理学的重要组成部分，因此我们提出的研究的后半部分将研究pannexin通道对于膀胱炎症的诱导或维持有何重要作用。为了研究这个问题，我们建议通过注射细菌脂多糖或环磷酰胺来诱导膀胱炎症，并研究将 pannexin 介导的 ATP 释放与膀胱病理学中观察到的排尿频率增加联系起来的信号通路。这些信号传导途径包括尿路上皮细胞表面嘌呤能受体的激活、NLRP3/NLRC4 炎性体的寡聚化以及 IL-1ß 受体刺激下游事件的激活，例如细胞旁通透性增加。我们希望这一目标的实验能够阐明涉及炎症的病理性膀胱疾病（例如间质性膀胱炎）的药物或基因治疗的新目标。