BK Channel Function and Regulation in Urinary Bladder Smooth Muscle

BK通道在膀胱平滑肌中的功能和调节

基本信息

批准号：
7699657
负责人：
Georgi V Petkov
金额：
$ 35.13万
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：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7699657
关键词：
1,2-diacylglycerol Abbreviations Acetylcholine Action Potentials Adenylate Cyclase Adrenergic Agents Adrenergic Receptor Animals Applications Grants Arts Basic Science Biological Bladder Bladder Dysfunction Calcium-Activated Potassium Channel Cavia Cell membrane Cells Clinical Collaborations Cyclic AMP-Dependent Protein Kinases Development Diglycerides Disease Electrophysiology (science)Engineering GTP-Binding Proteins Goals Health Human Human Activities ITPR1 gene Ion Channel Isometric Exercise Knockout Mice Knowledge Laboratories Lead Link Membrane Membrane Potentials Molecular Molecular Biology Mus Muscarinic M2 Receptor Muscarinic M3 Receptor Muscarinics Muscle Contraction Muscle function Muscle relaxation phase Operative Surgical Procedures Overactive Bladder Patch-Clamp Techniques Patients Pharmacotherapy Phospholipase C Physiological Population Positioning Attribute Potassium Channel Process Property Protein Kinase C Rattus Receptor Signaling Regulation Regulatory Pathway Relaxation Research Rest Role Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Sarcoplasmic Reticulum Scientist Signal Transduction Smooth Muscle Smooth Muscle Myocytes Techniques Testing Therapeutic Therapeutic Agents Thick Tissue Donors Tissues Urinary Incontinence Urine Urodynamics Whole Organism Work adrenergic cholinergic citrate carrier economic cost experience gene therapy genetic regulatory protein innovation insight large-conductance calcium-activated potassium channels mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics patch clamp patient population phospholamban public health relevance receptor research study single molecule urologic voltage

项目摘要

DESCRIPTION (provided by applicant): About 17% of the US population suffers from overactive bladder (OAB) and the associated economic cost is more than $26 billion per year. OAB is a poorly understood disorder characterized by increased urinary bladder smooth muscle (UBSM) contractility. In experimental animals, the large-conductance voltage-gated and Ca2+- activated K+ (BK) channel is a key regulator of UBSM membrane excitability and contractility. In general, inhibition of these ion channels leads to increased membrane excitability and contractility, whereas their activation hyperpolarizes the membrane and decreases contractility. However, the BK channel function and regulation in human UBSM is unknown. Our basic science research group, in collaboration with clinical scientists, is in a unique position to regularly utilize human UBSM tissues from donor patients to study BK channel function in humans and correlate the basic science findings with the clinical and urodynamic profile of the patients. Our long-term goal is to understand the mechanisms that regulate human UBSM BK channels under normal physiological conditions and to develop novel therapeutic strategies to control OAB. The objective of this application is to elucidate the physiological role and regulatory mechanisms of the BK channel in human UBSM contractility under normal physiological conditions. We will test the novel hypothesis that the BK channel determines the myogenic activity of human UBSM and it is regulated by cholinergic, 2- adrenergic, and differential Ca2+ signals with the following Aims: Aim 1. Elucidate the role of Ca2+ in the regulation of the BK channel in human UBSM myogenic activity; Aim 2. Elucidate the functional link between 2-adrenoceptors (2-ARs) and BK channels in UBSM; and Aim 3. Elucidate the functional link between muscarinic (M2 and M3) receptors and BK channels in UBSM. We will employ a combined approach, using state-of-the-art techniques, to determine the role of BK channels and their regulatory mechanisms in UBSM function from single molecules and isolated cells to intact tissue and the whole organism. Our team has the advantage of using full-thickness human UBSM tissues from open surgeries, which allows us to conduct advanced patch-clamp electrophysiology, functional studies on human UBSM contractility, and molecular biology experiments simultaneously. Thus, we can identify channel regulatory proteins, and then correlate BK channel activity with human UBSM contractility properties. Our research team's basic science and clinical expertise may lead to important translational observations. The proposed studies are expected to provide novel insights on BK channel function and regulation by cholinergic, 2-adrenergic, and Ca2+ signals in human UBSM. The results will have a significant impact on urological research with a strong potential to provide novel therapeutic approaches to help a large population of patients suffering from OAB. PUBLIC HEALTH RELEVANCE: Urinary bladder dysfunction is a major health issue in the US. Overactive bladder and related urinary incontinence are poorly understood disorders and effective therapeutic agents to control these conditions are lacking. Our basic science research group in collaboration with clinical scientists uses state-of-the-art techniques at the molecular, cellular, and tissue levels, to determine the role of cell membrane potassium ion channels as novel therapeutic targets to control urinary bladder dysfunction.

描述（由申请人提供）：大约17％的美国人口遭受过度活跃的膀胱（OAB），相关的经济成本每年超过260亿美元。 OAB是一种知名度不足的疾病，其特征是膀胱平滑肌（UBSM）收缩力增加。在实验动物中，大型电压门控和Ca2+活化的K+（BK）通道是UBSM膜兴奋性和收缩性的关键调节剂。通常，对这些离子通道的抑制会导致膜的兴奋性和收缩性增加，而它们的激活超极使膜并降低了收缩力。但是，人UBSM中的BK通道函数和调节尚不清楚。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组织来研究人类的BK通道功能，并将基础科学发现与患者的临床和尿动力学概况相关联。我们的长期目标是了解在正常生理条件下调节人UBSM BK通道的机制，并制定新的治疗策略来控制OAB。该应用的目的是阐明在正常生理条件下人类UBSM收缩性中BK通道的生理作用和调节机制。我们将检验以下新的假设：BK通道决定人类UBSM的肌原性活性，并由胆碱能，2-肾上腺素能和差分Ca2+信号调节，其目的是：目标1。阐明Ca2+在人类UBSM肌原活性中BK通道调节中的作用； AIM 2。阐明UBSM中2-肾上腺素受体（2-ARS）和BK通道之间的功能联系；和目标3。阐明UBSM中毒蕈碱（M2和M3）受体和BK通道之间的功能联系。我们将使用最先进的技术采用一种组合方法来确定BK通道及其调节机制在UBSM功能中的作用，从单分子和孤立的细胞到完整的组织和整个生物体。我们的团队的优点是使用开放手术的全厚度人UBSM组织，这使我们能够同时进行高级贴片钳电生理学，人类UBSM收缩性的功能研究以及分子生物学实验。因此，我们可以鉴定通道调节蛋白，然后将BK通道活性与人类UBSM收缩性特性相关联。我们的研究团队的基础科学和临床专业知识可能会导致重要的翻译观察。预计拟议的研究将在人UBSM中通过胆碱能，2-肾上腺素能和Ca2+信号提供有关BK通道功能和调节的新见解。该结果将对泌尿外科研究产生重大影响，具有强大的潜力，可以提供新的治疗方法，以帮助大量患有OAB的患者。公共卫生相关性：膀胱功能障碍是美国的主要健康问题。过度活跃的膀胱和相关的尿失禁是鲜为人知的疾病，缺乏有效的治疗剂来控制这些疾病。我们与临床科学家合作的基础科学研究小组在分子，细胞和组织水平上使用最先进的技术来确定细胞膜离子通道作为控制膀胱功能障碍的新型治疗靶标。