THE ROLE OF THE BKCA CHANNEL IN THE REGULATION OF UTERINE EXCITABILITY

BKCA 通道在子宫兴奋性调节中的作用

• 批准号: 7604805
• 负责人: Sarah K. England
• 金额: $ 0.06万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7604805
• 关键词: Accounting; Biochemical; Birth; Buffers; Calcium-Activated Potassium Channel; Cells; Cessation of life; Class; Computer Retrieval of Information on Scientific Projects Database; Funding; Grant; Human; Institution; Mediating; Mediator of activation protein; Membrane; Molecular; Morbidity - disease rate; Myometrial; Newborn Infant; Pattern; Play; Potassium Channel; Pregnancy; Premature Birth; Premature Labor; Prevention; Property; Rate; Regulation; Relaxation; Reporting; Research; Research Personnel; Resources; Role; Smooth Muscle; Source; Techniques; Tissues; Tocolysis; Tocolytic Agents; Transcript; United States National Institutes of Health; Uterine Contraction; beta adrenergic agent; myometrium; prevent; protein expression; research study; therapeutic target; uterine contractility; voltage

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Preterm births account for only 10% of all deliveries, however are associated with over 80% of newborn deaths and more than 95% of major newborn morbidity. Despite efforts toward prevention, there has been a 13% increase in the rate of preterm births over the past decade. The lack of understanding of the mechanism and regulation of uterine contraction has hampered progress towards an effective treatment for preterm labor. Currently used tocolytic agents have little effect in prolonging gestation, suggesting that other methods of preventing preterm labor should be investigated. One potential class of therapeutic targets that has been proposed is K+ channels due to their ability to potently buffer cell excitation. Electrophysiological reports have shown that myometrial cells contain a variety of K+ channel types that may be potential therapeutic targets, including large-conductance Ca2+-activated K+ channels (BKCa channels). BKCa channels play a significant role in uterine contractility. Block of BKCa channels depolarizes myometrial cells and increases contractile activity, while openers induce uterine relaxation. Additionally, these channels are activated by beta-adrenergic agents and other uterine relaxants. A channel similar to the BKCa channel in conductance properties, but lacking its voltage- and Ca2+ - sensitivity, has been described in human myometrium in labor, and may represent the BKCa channel uncoupled from its beta subunit, which mediates Ca2+ - and voltage-sensitivity to this channel. Therefore, one potential aspect of BKCa channel regulation that should be investigated is the role that the recently identified accessory beta subunits may play in modulating the properties and function of these channels during pregnancy. The objective of this proposal is to determine the molecular architetcture of the BKCa channel during parturition and to elucidate the role that K+ channel beta subunits play in regulating uterine activity. The specific aims are to: 1) determine the expression pattern of the human BKCa channel transcript during parturition; 2) characterize BKCa alpha and beta subunit protein expression in myometrial smooth muscle during parturition; and 3) characterize BKCa channel alpha and beta subunit expression and assembly in human uterine tissue at parturition. These experiments will use molecular and biochemical approaches to define the BKCa channel mechanisms which regulate uterine excitability. The studies will determine the importance of this channel during parturition, and identify the role of this channel as a potential mediator of myometrial membrane repolarization and as a possible target for tocolytic therapy.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 早产仅占所有分娩的10％，但是与80％的新生儿死亡和超过95％的新生儿发病率有关。 尽管为预防而做出了努力，但在过去十年中，早产率增加了13％。 缺乏对子宫收缩机制和调节的理解，阻碍了对早产的有效治疗的进步。 目前使用的溶烧剂对延长妊娠几乎没有影响，这表明应研究其他预防早产的方法。 提出的一种潜在的治疗靶标是K+通道，因为它们具有有效的缓冲细胞激发能力。 电生理报告表明，肌层细胞包含各种可能是潜在治疗靶标的K+通道类型，包括大传导CA2+激活的K+通道（BKCA通道）。 BKCA渠道在子宫收缩性中起着重要作用。 BKCA通道的块去极化细胞并增加收缩活性，而开瓶器会引起子宫弛豫。 此外，这些通道被β-肾上腺素能剂和其他子宫松弛剂激活。 与BKCA通道相似的通道，但缺乏其电压和Ca2+ - 灵敏度，在人体肌层中已经描述了劳动力的敏感性，并且可能代表与其beta亚基未偶联的BKCA通道，该bebca通道介导了Ca2+ - 与该通道的电压敏感性。 因此，应该研究的BKCA通道调节的一个潜在方面是最近确定的辅助beta亚基在调节怀孕期间这些通道的性质和功能方面的作用。 该提案的目的是确定分娩过程中BKCA通道的分子结构，并阐明K+通道β亚基在调节子宫活性中的作用。 具体目的是：1）确定分娩期间人类BKCA通道转录的表达模式； 2）表征分娩过程中肌层平滑肌中BKCAα和β亚基蛋白的表达； 3）表征分娩时人子宫组织中BKCA通道α和β亚基表达和组装。 这些实验将使用分子和生化方法来定义调节子宫兴奋性的BKCA通道机制。 这些研究将确定该通道在分娩过程中的重要性，并确定该通道作为肌层膜复极化的潜在介体的作用，并成为溶血疗法的可能目标。