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

• 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
• 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

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）：约17%的美国人口患有膀胱过度活动症（OAB），每年相关的经济成本超过260亿美元。OAB是一种知之甚少的疾病，其特征在于膀胱平滑肌（UBSM）收缩性增加。在实验动物中，大电导电压门控和Ca 2+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，这些离子通道的抑制导致膜兴奋性和收缩性增加，而它们的激活使膜超极化并降低收缩性。然而，BK通道在人类UBSM中的功能和调节是未知的。我们的基础科学研究小组与临床科学家合作，处于一个独特的地位，定期利用供体患者的人类UBSM组织研究人类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在正常生理条件下调节人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UBSM的生肌活性，并且它受胆碱能、β 2-肾上腺素能和差异Ca 2+信号的调节，目的如下：目的1。阐明Ca 2+在人UBSM肌源性活性中BK通道调节中的作用;目的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;和Aim 3。阐明UBSM中毒蕈碱（M2和M3）受体与BK通道之间的功能联系。我们将采用一种综合的方法，使用最先进的技术，以确定BK通道的作用及其在UBSM功能的调节机制，从单个分子和分离的细胞到完整的组织和整个生物体。我们的团队具有使用来自开放手术的全层人类UBSM组织的优势，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，我们可以鉴定通道调节蛋白，然后将BK通道活性与人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导致重要的转化观察。这些研究有望为人类UBSM中BK通道的功能和胆碱能、2-肾上腺素能和Ca 2+信号的调节提供新的见解。这些结果将对泌尿外科研究产生重大影响，并有很大的潜力提供新的治疗方法，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一个主要健康问题。膀胱过度活动症和相关的尿失禁是知之甚少的疾病和有效的治疗药物来控制这些条件是缺乏的。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型治疗靶点的作用。