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：
8322549
负责人：
Georgi V Petkov
金额：
$ 31.09万
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 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8322549
关键词：
1,2-diacylglycerol Abbreviations Acetylcholine Action Potentials Adenylate Cyclase Adrenergic Agents Adrenergic Receptor Animals Applications Grants 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 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% 的美国人口患有膀胱过度活动症 (OAB)，每年相关的经济损失超过 260 亿美元。 OAB 是一种人们知之甚少的疾病，其特征是膀胱平滑肌 (UBSM) 收缩力增加。在实验动物中，大电导电压门控和 Ca2+ 激活的 K+ (BK) 通道是 UBSM 膜兴奋性和收缩性的关键调节因子。一般来说，抑制这些离子通道会导致膜兴奋性和收缩性增加，而它们的激活会使膜超极化并降低收缩性。然而，人类 UBSM 中的 BK 通道功能和调节尚不清楚。我们的基础科学研究小组与临床科学家合作，处于独特的地位，可以定期利用来自捐赠患者的人类 UBSM 组织来研究人类 BK 通道功能，并将基础科学发现与患者的临床和尿动力学特征相关联。我们的长期目标是了解正常生理条件下调节人类 UBSM BK 通道的机制，并开发新的治疗策略来控制 OAB。本申请的目的是阐明正常生理条件下BK通道在人UBSM收缩力中的生理作用和调节机制。我们将测试新的假设，即 BK 通道决定人类 UBSM 的生肌活性，并且它受到胆碱能、2-肾上腺素能和差异 Ca2+ 信号的调节，目的如下：目标 1. 阐明 Ca2+ 在调节人类 UBSM 生肌活性中的 BK 通道；目标 2. 阐明 UBSM 中 2-肾上腺素受体 (2-AR) 和 BK 通道之间的功能联系；目标 3. 阐明 UBSM 中毒蕈碱（M2 和 M3）受体与 BK 通道之间的功能联系。我们将采用综合方法，利用最先进的技术，确定 BK 通道的作用及其在 UBSM 功能（从单分子和分离细胞到完整组织和整个生物体）中的调节机制。我们团队的优势在于使用来自开放手术的全层人类 UBSM 组织，这使我们能够同时进行先进的膜片钳电生理学、人类 UBSM 收缩性的功能研究和分子生物学实验。因此，我们可以识别通道调节蛋白，然后将 BK 通道活性与人类 UBSM 收缩特性相关联。我们的研究团队的基础科学和临床专业知识可能会带来重要的转化观察结果。拟议的研究有望为人类 UBSM 中胆碱能、2-肾上腺素能和 Ca2+ 信号的 BK 通道功能和调节提供新的见解。研究结果将对泌尿外科研究产生重大影响，并有很大潜力提供新的治疗方法来帮助大量患有 OAB 的患者。公众健康相关性：膀胱功能障碍是美国的一个主要健康问题。膀胱过度活动症和相关的尿失禁是人们知之甚少的疾病，并且缺乏控制这些病症的有效治疗药物。我们的基础科学研究小组与临床科学家合作，在分子、细胞和组织水平上使用最先进的技术，以确定细胞膜钾离子通道作为控制膀胱功能障碍的新治疗靶点的作用。