Molecular and Functional Mechanisms of Purinergic Relaxation in Detrusor Muscle

逼尿肌嘌呤能松弛的分子和功能机制

基本信息

批准号：
8917943
负责人：
SANG Don KOH
金额：
$ 31.21万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8917943
关键词：
Address Adult Adverse effects Affect Agonist Animal Model Antibodies Area Binding Bladder Bladder Control Calcium-Activated Potassium Channel Cells Collecting Cell Complex Coupled Coupling Defect Down-Regulation Dyes Engineering Feeling Fluorescence-Activated Cell Sorting Frequencies G-Protein-Coupled Receptors Gap Junctions Gastrointestinal tract structure Genes Genetic Health Image Investigation Ion Channel Lead Measurement Mediating Membrane Potentials Modeling Molecular Motor Motor Neurons Mus Muscarinic Acetylcholine Receptor Muscarinic Antagonists Muscarinics Muscle Muscle Cells Nerve Fibers Neurons Nocturia Overactive Bladder P2X-receptor PDGFRB gene Pathway interactions Patients Pharmacological Treatment Phenotype Physiology Platelet-Derived Growth Factor Receptor Population Purines Quality of life Receptor Activation Receptor Cell Regulation Relaxation Reporter Reporting Research Personnel Role Sensory Signal Pathway Signal Transduction Smooth Muscle Myocytes Symptoms Transcript United States Urge Incontinence Urodynamics cell motility cholinergic common treatment density detrusor muscle interstitial cell molecular phenotype neuroregulation neurotransmission novel premature purine receptor relating to nervous system response targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Overactive bladder is a highly prevalent condition, affecting approximately 33 million adults in the United States. Symptoms include frequency, urgency, urge incontinence, or nocturia. As bladder volume increases, involuntary contractions of the detrusor muscle are often associated with overactive bladder. The mechanisms underlying these involuntary contractions have not yet been fully elucidated. Despite the considerable impact this condition has on patients' quality of life, the pharmacological treatment of overactive bladder still remains controversial because of the adverse effects of commonly using anti-muscarinic agents. The purinergic- mediated responses can be another targeting for the treatment of detrusor over activity (DO). P2X receptors mediate contraction and P2Y receptors involve relaxation. P2X receptors are highly expressed in smooth muscle cells but limited expression of P2Y receptors. Thus, we hypothesize that purinergic relaxation might be mediated by activation of P2Y receptors in specialized cells. P2Y receptors are G-protein coupled receptors (GPCR). GPCR modulate the activity of ion channels. The activation of ion channels by P2Y receptors has not been explored in detrusor muscle. We will characterize the functional expression of P2Y receptors, the subsequent increase in intracellular Ca2+ and modulation of Ca2+- activated K+ channels which are involved in detrusor relaxation. Functional expression of small conductance Ca2+-activated K+ (SK) channels in the detrusor muscle has been reported. However the current density of SK channels in detrusor smooth muscle cell was almost negligible at negative membrane potentials. We hypothesize that the expression and activation of SK channels in specialized cells within the detrusor wall are involved in the hyperpolarization and relaxation responses. Recently, our lab reported that specific classes of interstitial cells exist in the bladder. These interstitial cells are identified using antibodies aainst platelet-derived growth factor receptor-� (PDGFR-�+). These cells were distributed throughout detrusor muscle, and were in close apposition with intramural nerve fibers. PDGFR-�+ cells have been described in the gastrointestinal tract and are implicated in purinergic inhibitory neurotransmission. We hypothesize that PDGFR-�+ cells have functional roles on the detrusor purinergic relaxation and abnormality of PDGFR-�+ cells induces DO. In summary, we will characterize a novel population of cells that generate the purinergic inhibitory component of bladder neurotransmission. Isolation of PDGFR-�+ cells and functional study of PDGFR-�+ cells will allow more detailed understanding of purinergic neurotransmission and may reveal new targets for therapies to control detrusor motility. This information will open up important novel areas of investigation in urodynamics physiology and expand new venue of treatment of bladder over activity.

描述（由申请人提供）：膀胱过度活动症是一种非常普遍的疾病，影响着美国大约 3300 万成年人，症状包括尿频、尿急、急迫性尿失禁或夜尿，随着膀胱容量的增加，逼尿肌经常会出现不自主收缩。尽管这种情况对患者的生活质量有相当大的影响，但膀胱过度活动症的药物治疗尚未完全阐明。由于常用抗毒蕈碱药物的副作用，膀胱仍然存在争议。嘌呤能介导的反应可能是治疗逼尿肌过度活动（DO）的另一个靶标，P2X 受体介导收缩，P2Y 受体涉及松弛。在平滑肌细胞中高表达，但 P2Y 受体表达有限，因此，我们认为嘌呤能松弛可能是通过特殊细胞中 P2Y 受体的激活来介导的。 G 蛋白偶联受体 (GPCR) 通过 P2Y 受体调节离子通道的活性，但尚未在逼尿肌中进行研究。参与逼尿肌松弛的 Ca2+ 激活 K+ 通道的调节已被证实是逼尿肌中小电导 Ca2+ 激活 K+ (SK) 通道的功能性表达。然而，近来，我们发现逼尿肌壁内特殊细胞中 SK 通道的表达和激活与超极化和松弛反应有关。我们的实验室报告说，膀胱中存在特定类型的间质细胞，这些间质细胞是使用抗血小板衍生生长因子受体-�（PDGFR-�+）的抗体进行识别的。 PDGFR-�+ 细胞遍布逼尿肌，并与胃肠道中的壁内神经纤维紧密相连，并且与嘌呤能抑制性神经传递有关。我们发现 PDGFR-�+ 细胞对逼尿肌嘌呤能松弛具有功能作用。 PDGFR-�+ 细胞的异常会诱导 DO 总之，我们将表征产生嘌呤能抑制成分的新型细胞群。 PDGFR-�+ 细胞的分离和 PDGFR-�+ 细胞的功能研究将有助于更详细地了解嘌呤能神经传递，并可能揭示控制逼尿肌运动的治疗的新靶标。这些信息将开辟重要的新研究领域。尿动力学生理学并拓展膀胱过度活动症治疗的新领域。