Regulation of Urinary Bladder Smooth Muscle by K+ Channels

K 通道对膀胱平滑肌的调节

基本信息

批准号：
8089512
负责人：
Georgi V Petkov
金额：
$ 21.35万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8089512
关键词：
Abbreviations Action Potentials Address Adenylate Cyclase Adrenergic Receptor Adverse effects Affect Animals Apamin Applications Grants Basic Science Bee Venoms Bladder Bladder Tissue Calcium-Activated Potassium Channel Cell Separation Cell membrane Cells Clinical Collaborations Color Cyclic AMP-Dependent Protein Kinases Cystectomy Dimensions Disease Electrophysiology (science)Elements Environment Frequencies Functional disorder GTP-Binding Protein alpha Subunits, Gs Gene Expression Goals Health Human Human Genome Individual Ion Channel Knowledge Lead Malignant neoplasm of urinary bladder Membrane Methodology Molecular Molecular Biology Monitor Muscarinics Muscle Contraction Muscle function Muscle relaxation phase Mutation Nature Nocturia Operative Surgical Procedures Overactive Bladder Pathway interactions Patients Peptides Pharmacotherapy Physiological Physiology Play Population Positioning Attribute Potassium Channel Probability Procedures Process Property Protein Kinase Rattus Receptor Signaling Regulation Relaxation Research Research Project Grants Research Proposals Reverse Transcriptase Polymerase Chain Reaction Role Ryanodine Receptor Calcium Release Channel Sarcoplasmic Reticulum Scientist Signal Transduction Smooth Muscle Smooth Muscle Myocytes Symptoms Techniques Testing Therapeutic Intervention Thick Time Tissue Donors Tissues Urinary Incontinence Urine Urodynamics Urologist Whole Organism Work economic cost experience genetic regulatory protein inhibitor/antagonist innovation lower urinary tract symptoms new therapeutic target novel novel strategies novel therapeutics patch clamp phospholamban potassium ion programs public health relevance research study single molecule success voltage

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to add a new dimension to our understanding of the mechanisms that regulate human urinary bladder function under normal and pathological conditions and to develop novel therapeutic strategies to control overactive bladder (OAB). OAB, detrusor overactivity (DO), and related urinary incontinence (UI), which affects about 17% of the US population, is characterized with increased urinary bladder smooth muscle (UBSM) contractility. Potassium ion (K+) channels, the most diverse ion channel superfamily, are key regulators of UBSM cell membrane excitability and action potentials that determine the phasic nature of UBSM contractility. In general, inhibition of these ion channels leads to increased membrane excitability and phasic contractions, whereas their activation hyperpolarizes the cell membrane and decreases contractility. Our basic science research group, in collaboration with clinical scientists, is in a unique position to regularly make use of human UBSM tissues from donor patients in order to study K+ channel function in humans and correlate the basic science findings with the urodynamic profile of the patients. The overall goal of this project is to illuminate the role of two major K+ channels, the small conductance Ca2+-activated (SK) K+ channel and the intermediate conductance Ca2+-activated K+ (IK) channel, and their regulatory mechanisms in human UBSM under normal and pathological conditions. This proposal will test the novel hypothesis that the SK/IK channels are major regulators of human UBSM excitability and contractility, and therefore changes in the SK/IK channels activity or regulatory mechanisms may lead to OAB/DO and related UI. Furthermore, the SK/IK channels may represent an opportunity for novel pharmacological manipulation and therapeutic intervention in human UBSM. Specific Aim 1 will elucidate the role of the SK/IK channels in UBSM function under normal and pathophysiological conditions; and Specific Aim 2 will elucidate the mechanism by which 2-adrenergic receptors signal the SK/IK channels to promote UBSM relaxation. This project will use UBSM tissues from patients with asymptomatic bladder (AUA symptom score <8; cystectomy for bladder cancer), OAB (defined as increased frequency, urgency, and nocturia), and DO (defined as urodynamically demonstrated overactivity). We will employ a combined approach, using state-of- the-art techniques, to determine the role of SK/IK channels and their regulatory mechanisms in UBSM function from single molecules and isolated cells to intact tissue and the whole organism. PUBLIC HEALTH RELEVANCE: Overactive bladder (OAB) affects about 17% of the US population, and is characterized by increased urinary bladder smooth muscle contractility. Our project will exploit specific potassium channels in urinary bladder tissue to develop novel therapies to control or alleviate OAB.

描述（由申请人提供）：该项目的长期目标是为我们对在正常和病理条件下调节人类膀胱功能的机制的理解增加一个新维度，并制定新的治疗策略来控制过度活跃的膀胱（OAB））。 OAB，影响约17％的美国人群的OAB，其过度活动（DO）和相关的尿失禁（UI）的特征是尿膀胱平滑肌（UBSM）的收缩力增加。钾离子（K+）通道，最多样化的离子通道超家族，是UBSM细胞膜兴奋性和动作电位的关键调节剂，这些调节剂决定了UBSM收缩力的阶段性质。通常，对这些离子通道的抑制会导致膜兴奋性和阶段收缩增加，而它们的激活使细胞膜超极并降低了收缩力。我们的基础科学研究小组与临床科学家合作，处于独特的位置，可以定期利用供体患者的人类UBSM组织，以便研究人类的K+通道功能，并将基础科学发现与患者的尿动力学概况相关联。该项目的总体目标是阐明两个主要的K+通道的作用，小电导Ca2+激活（SK）K+通道和中间电导Ca2+激活的K+（IK）通道及其在正常情况下的调节机制和病理状况。该建议将检验新的假设，即SK/IK通道是人类UBSM兴奋性和收缩性的主要调节剂，因此SK/IK通道活动或调节机制的变化可能导致OAB/DO和相关的UI。此外，SK/IK通道可能代表了人类UBSM中新型药理操作和治疗干预的机会。具体的目标1将阐明在正常和病理生理条件下SK/IK通道在UBSM功能中的作用；具体目标2将阐明2-肾上腺素能受体向SK/IK通道发出促进UBSM松弛的机制。该项目将使用无症状膀胱患者的UBSM组织（AUA症状评分<8；膀胱癌的膀胱切除术），OAB（定义为增加的频率，紧迫性和夜尿），并且DO（定义为泌尿动力学表现出过度运动）。我们将使用最先进的技术采用合并的方法来确定SK/IK通道及其调节机制在UBSM功能中的作用，从单分子和分离的细胞到完整的组织和整个生物体。公共卫生相关性：过度活跃的膀胱（OAB）影响了美国人口的17％，其特征是膀胱平滑肌收缩性增加。我们的项目将利用泌尿膀胱组织中的特定钾通道来开发用于控制或减轻OAB的新型疗法。