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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：
8587122
负责人：
Georgi V Petkov
金额：
$ 0.15万
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/8587122
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)GTP-Binding Proteins Genetic Engineering 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.

描述（由申请人提供）：约17%的美国人口患有膀胱过动症（OAB），相关的经济成本每年超过260亿美元。OAB是一种鲜为人知的疾病，其特征是膀胱平滑肌（UBSM）收缩性增加。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增加膜的兴奋性和收缩性，而它们的激活会使膜超极化并降低收缩性。然而，BK通道在人类UBSM中的功能和调控尚不清楚。我们的基础科学研究小组与临床科学家合作，处于一个独特的位置，定期利用来自供体患者的人类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联系起来。我们的长期目标是了解在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。本应用程序的目的是阐明在正常生理条件下BK通道在人类UBSM收缩性中的生理作用和调节机制。我们将测试新的假设，即BK通道决定了人类UBSM的肌生成活动，并受胆碱能、2-肾上腺素能和差异Ca2+信号的调节，目的如下：阐明Ca2+在调节BK通道在人UBSM肌生成活动中的作用；目标2。阐明2-肾上腺素受体（2-ARs）和BK通道在UBSM中的功能联系；和Aim 3。阐明毒蕈碱（M2和M3）受体和BK通道在UBSM中的功能联系。我们将采用综合方法，使用最先进的技术，确定BK通道及其调控机制在从单分子和分离细胞到完整组织和整个生物体的UBSM功能中的作用。我们团队的优势是使用开放手术的全层人体UBSM组织，这使我们能够同时进行先进的膜片钳电生理学，人体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收缩性特性联系起来。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转化观察。拟议的研究有望为BK通道功能和人类UBSM中胆碱能、2-肾上腺素能和Ca2+信号的调节提供新的见解。该结果将对泌尿学研究产生重大影响，并有可能为大量OAB患者提供新的治疗方法。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular expression and pharmacological evidence for a functional role of kv7 channel subtypes in Guinea pig urinary bladder smooth muscle.

DOI：
10.1371/journal.pone.0075875
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Afeli SA;Malysz J;Petkov GV
通讯作者：
Petkov GV

BK channel-mediated relaxation of urinary bladder smooth muscle: a novel paradigm for phosphodiesterase type 4 regulation of bladder function.

BK 通道介导的膀胱平滑肌松弛：4 型磷酸二酯酶调节膀胱功能的新范例。

DOI：
10.1124/jpet.113.210708
发表时间：
2014
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
0
作者：
Xin,Wenkuan;Li,Ning;Cheng,Qiuping;Petkov,GeorgiV
通讯作者：
Petkov,GeorgiV

Selective inhibition of phosphodiesterase 1 relaxes urinary bladder smooth muscle: role for ryanodine receptor-mediated BK channel activation.

选择性抑制磷酸二酯酶 1 可放松膀胱平滑肌：兰尼碱受体介导的 BK 通道激活的作用。

DOI：
10.1152/ajpcell.00162.2012
发表时间：
2012
期刊：
American journal of physiology. Cell physiology
影响因子：
0
作者：
Xin,Wenkuan;Soder,RupalP;Cheng,Qiuping;Rovner,EricS;Petkov,GeorgiV
通讯作者：
Petkov,GeorgiV

Constitutive PKA activity is essential for maintaining the excitability and contractility in guinea pig urinary bladder smooth muscle: role of the BK channel.

组成性 PKA 活性对于维持豚鼠膀胱平滑肌的兴奋性和收缩性至关重要：BK 通道的作用。

DOI：
10.1152/ajpcell.00167.2014
发表时间：
2014
期刊：
American journal of physiology. Cell physiology
影响因子：
0
作者：
Xin,Wenkuan;Li,Ning;Cheng,Qiuping;Fernandes,VitorS;Petkov,GeorgiV
通讯作者：
Petkov,GeorgiV

Functional link between muscarinic receptors and large-conductance Ca2+ -activated K+ channels in freshly isolated human detrusor smooth muscle cells.

DOI：
10.1007/s00424-014-1537-8
发表时间：
2015-04
期刊：
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
影响因子：
4.5
作者：
Parajuli, Shankar P.;Hristov, Kiril L.;Cheng, Qiuping;Malysz, John;Rovner, Eric S.;Petkov, Georgi V.
通讯作者：
Petkov, Georgi V.