Calcium activated chloride channel modulation of myometrial excitability
钙激活氯离子通道调节子宫肌层兴奋性
基本信息
- 批准号:9413206
- 负责人:
- 金额:$ 32.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-10 至 2021-01-31
- 项目状态:已结题
- 来源:
- 关键词:Activities of Daily LivingAdrenergic ReceptorAgonistAreaAttenuatedAutomobile DrivingBathingBiologyBirthCalciumCalcium Channel BlockersCalcium OscillationsCell membraneCellsCenters for Disease Control and Prevention (U.S.)Cesarean sectionChloride ChannelsChloridesClinicalConfocal MicroscopyCouplingDataDefectDiscipline of obstetricsDyesElectrodesElectrophysiology (science)Enterobacteria phage P1 Cre recombinaseF-ActinFamilyFrequenciesGTP-Binding ProteinsGenesGeneticHarvestHealth ExpendituresHealthcareHumanIn VitroIncidenceIon ChannelLinkMeasurementMeasuresMechanicsMembrane PotentialsMolecularMolecular TargetMorbidity - disease rateMusMuscleMuscle relaxation phaseMyometrialNifedipineOrganOxytocinPatientsPharmacologyPlayPregnancyPremature BirthPremature LaborPreparationProteinsPublishingRattusRelaxationResearchResearch PersonnelRestRoleSamplingSarcoplasmic ReticulumSecond Messenger SystemsSignal PathwaySliceSmall Interfering RNASmooth MuscleStretchingTachyphylaxisTamoxifenTechniquesTerbutalineTherapeuticTissuesTocolysisTocolytic AgentsUnited StatesUterine ContractionUterine Smooth Muscle ExcitabilityWorkbaseexperimental studyextracellularglobal healthin vivoinsightknock-downmathematical modelmuscle physiologymyometriumnovelpregnantprematurepublic health relevancereceptorrelease of sequestered calcium ion into cytoplasmtherapeutic targetuterine contractilityuterine smooth muscle celluterine smooth muscle contraction
项目摘要
DESCRIPTION (provided by applicant): Preterm birth is an enormous, growing global health care challenge. In the United States, >520,000 preterm births occur each year, many of which are associated with substantial morbidity. Although research has made insights into the mechanisms contributing to pre-term labor (PTL), the therapeutic armamentarium for PTL remains limited and inefficacious. However, the recent identification of the anoctamin (ANO) family of calcium-activated chloride channels has revolutionized our understanding of how these chloride channels play integral roles in modulating membrane potential, pacing, and contractility in other smooth muscle tissues. In this current proposal we establish ANO1's functional importance in the contractility and pacing frequency of human uterine smooth muscle (USM), determine the feasibility of using ANO1 as a therapeutic target to attenuate human USM contractions in vitro, and explore the underlying molecular mechanisms responsible for these beneficial effects. In particular, studies will span whole tissue functional organ bath experiments
on fresh human myometrium strips harvested from late gestation c-section patients to mechanistic cell based studies focusing on the role of these channels on driving USM cell membrane potential, in calcium handling and filamentous-actin dynamics. We will employ a wide range of techniques including confocal microscopy, electrophysiology, in vivo and in vitro gene editing, and pharmacological antagonist strategies to establish the role of this channel family in human uterine contractility. The work is purposed to not only establish the importance of this channel in normal uterine smooth muscle physiology, but to also ascertain if it may serve as a new target to treat pre-mature contractions. As such, the potential for a highly translational
therapy for pre- term labor exists.
描述(由申请人提供):早产是一个巨大且日益严重的全球医疗保健挑战。在美国,每年发生超过 520,000 例早产,其中许多与高发病率有关。尽管研究已经深入了解了早产 (PTL) 的机制,但 PTL 的治疗手段仍然有限且无效。然而,最近对钙激活氯离子通道的 anoctamin (ANO) 家族的鉴定彻底改变了我们对这些氯离子通道如何在调节其他平滑肌组织的膜电位、起搏和收缩性方面发挥不可或缺作用的理解。在当前的提案中,我们确定了 ANO1 在人子宫平滑肌 (USM) 的收缩性和起搏频率中的功能重要性,确定了使用 ANO1 作为治疗靶点在体外减弱人 USM 收缩的可行性,并探索了导致这些有益作用的潜在分子机制。特别是,研究将涵盖整个组织功能器官浴实验
对从妊娠晚期剖腹产患者采集的新鲜人类子宫肌条进行基于机械细胞的研究,重点关注这些通道在驱动 USM 细胞膜电位、钙处理和丝状肌动蛋白动力学中的作用。我们将采用多种技术,包括共聚焦显微镜、电生理学、体内和体外基因编辑以及药理学拮抗剂策略来确定该通道家族在人类子宫收缩力中的作用。这项工作的目的不仅在于确定该通道在正常子宫平滑肌生理学中的重要性,还在于确定它是否可以作为治疗早产宫缩的新靶点。因此,高度转化的潜力
存在早产治疗方法。
项目成果
期刊论文数量(0)
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George Gallos其他文献
George Gallos的其他文献
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{{ truncateString('George Gallos', 18)}}的其他基金
Calcium activated chloride channel modulation of myometrial excitability
钙激活氯离子通道调节子宫肌层兴奋性
- 批准号:
9256225 - 财政年份:2016
- 资助金额:
$ 32.32万 - 项目类别:
THERAPEUTIC TARGETING OF THE GABAA CHANNEL ON AIRWAY SMOOTH MUSCLE
GABAA 通道对气道平滑肌的治疗靶向
- 批准号:
8317666 - 财政年份:2010
- 资助金额:
$ 32.32万 - 项目类别:
THERAPEUTIC TARGETING OF THE GABAA CHANNEL ON AIRWAY SMOOTH MUSCLE
GABAA 通道对气道平滑肌的治疗靶向
- 批准号:
8120856 - 财政年份:2010
- 资助金额:
$ 32.32万 - 项目类别:
THERAPEUTIC TARGETING OF THE GABAA CHANNEL ON AIRWAY SMOOTH MUSCLE
GABAA 通道对气道平滑肌的治疗靶向
- 批准号:
7871765 - 财政年份:2010
- 资助金额:
$ 32.32万 - 项目类别:
THERAPEUTIC TARGETING OF THE GABAA CHANNEL ON AIRWAY SMOOTH MUSCLE
GABAA 通道对气道平滑肌的治疗靶向
- 批准号:
8512739 - 财政年份:2010
- 资助金额:
$ 32.32万 - 项目类别:
THERAPEUTIC TARGETING OF THE GABAA CHANNEL ON AIRWAY SMOOTH MUSCLE
GABAA 通道对气道平滑肌的治疗靶向
- 批准号:
8716771 - 财政年份:2010
- 资助金额:
$ 32.32万 - 项目类别:
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