Molecular Physiology of the Na-K-Cl Cotransporter
Na-K-Cl 协同转运蛋白的分子生理学
基本信息
- 批准号:7901772
- 负责人:
- 金额:$ 9.97万
- 依托单位:
- 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:2009-09-11 至 2010-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAmino Acid TransporterBehaviorBiochemicalBumetanideCarrier ProteinsCationsCell VolumesCell membraneCellsCerebral EdemaChargeChloride IonChloridesCysteineCystic FibrosisDefectDiagnosisDiagnosticDiarrheaDimerizationDiseaseDiureticsEpitheliumEvaluationFamilyFluorescence Resonance Energy TransferFurosemideGoalsHomeostasisHypertensionIndividualIon TransportIonsKidneyLabelLeadMechanicsMediatingMembrane Transport ProteinsModelingMolecularMolecular StructureMonitorMovementMusMutagenesisNa(+)-K(+)-Exchanging ATPaseNeuronsOpticsOrganPharmaceutical PreparationsPhysiological ProcessesPhysiologyPlayPolycystic Kidney DiseasesPotassium ChannelPotassium ChlorideProcessProtein IsoformsProteinsRegulationReporterReportingResearchResolutionRoleSalivary GlandsScanningSideSignal TransductionSiteSmall Interfering RNASodiumSodium ChlorideStrokeStructureStructure of choroid plexusStructure-Activity RelationshipTestingTherapeutic AgentsTissuesTransgenic MiceTransgenic OrganismsTransmembrane DomainWorkabsorptionbasechloride-cotransporter potassiumclomeleondesigndimermembermouse modelnervous system disorderpolarized cellresearch studysensortissue culture
项目摘要
DESCRIPTION (provided by applicant): The Na-K-Cl cotransporter (NKCC) is a plasma membrane transport protein that plays a central role in cellular homeostasis. In non-polarized cells including neurons the NKCC1 isoform is involved in regulation of intracellular chloride and cell volume, and in secretory epithelia, NKCC1 functions together with Cl channels, the Na pump, and K channels to bring about regulated salt movement. In the mammalian kidney another isoform, NKCC2, mediates salt absorption and is the site of action of the loop diuretic drugs furosemide and bumetanide. NKCCs are members of the cation-chloride cotransporter family, and of the APC superfamily of transporters. The long term goal of this project, which focuses on NKCC1, is to understand the molecular mechanism of the cotransporter, including the structural and functional features underlying ion translocation and its regulation, and the significance of the transporter in cell and organ function. The research is directly relevant to the understanding, diagnosis, and treatment of ion transport diseases and disease conditions including hypertension, polycystic kidney disease, secretory diarrhea, cerebral edema associated with stroke, and cystic fibrosis. The Specific Aims of the project are: 1) To examine the structure and function of the transport protein, utilizing FRET probes to look at cotransporter activation and conformational changes, testing a hypothesis of functionally interacting dimer partners, using cysteine scanning mutagenesis to investigate potential reentrant pore loops, and elucidating the mechanism of the activation switch in CCCs; 2) To further elucidate the mechanism of regulation of NKCC1 by cell volume and intracellular [Cl-] utilizing a transgenic reporter mouse encoding a fluorescent sensor of intracellular Cl- concentration and transporter activation. Diseases and disease conditions including hypertension, cerebral edema, polycystic kidney disease, secretory diarrhea, cystic fibrosis, and some diseases of the nervous system involve defects or overactivity of the cellular machinery that is responsible for salt movements across cell membranes. This research is directed to understanding one part of that cellular machinery, a protein called the Na-K-Cl cotransporter (or NKCC) that is responsible for handling coordinated sodium, potassium and chloride movements. By understanding the molecular structure of the protein, the mechanics of its action, and the mechanism of its regulation we will be better able to design diagnostic and therapeutic agents and treat these disease states.
描述(由申请人提供):NA-K-CL共转运蛋白(NKCC)是一种质膜转运蛋白,在细胞稳态中起着核心作用。在包括神经元在内的非偏振细胞中,NKCC1同工型参与细胞内氯化物和细胞体积的调节,在分泌上皮中,NKCC1与CL通道,NA泵和K通道一起起作用,以引起调节的盐运动。在哺乳动物肾脏中,另一种同工型NKCC2介导了盐的吸收,并且是环状利尿药源自速膜剂和bumetanide的作用部位。 NKCC是阳离子 - 氯化物共转运蛋白家族的成员,也是转运蛋白的APC超家族的成员。该项目的长期目标(着重于NKCC1)是了解共转运蛋白的分子机制,包括离子易位及其调控的结构和功能特征,以及转运蛋白在细胞和器官功能中的重要性。这项研究与对离子转运疾病和疾病疾病的理解,诊断和治疗直接相关,包括高血压,多囊性肾脏疾病,分泌性腹泻,与中风相关的脑水肿和囊性纤维化。该项目的具体目的是:1)检查运输蛋白的结构和功能,利用FRET探针来查看共转运蛋白的激活和构象变化,测试功能相互作用的二聚体伴侣的假设,使用半胱氨酸扫描诱变来研究潜在的重新剂量。孔回路,并阐明CCC中激活开关的机理; 2)通过细胞体积和细胞内[Cl-]进一步阐明了NKCC1调节的机理,利用了编码细胞内CL-浓度和转运蛋白激活的荧光传感器的转基因报告基因小鼠。疾病和疾病疾病,包括高血压,脑水肿,多囊性肾脏疾病,分泌性腹泻,囊性纤维化以及神经系统的某些疾病涉及导致跨细胞膜盐运动的细胞机械的缺陷或过度活动。这项研究旨在理解该细胞机械的一部分,该蛋白质称为Na-k-Cl共转运蛋白(或NKCC),该蛋白质负责处理协调的钠,钾和氯化物运动。通过了解蛋白质的分子结构,其作用的力学以及调节的机制,我们将更好地设计诊断和治疗剂并治疗这些疾病状态。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('BLISS FORBUSH', 18)}}的其他基金
Function and High-Resolution of an APC superfamily amino acid transporter
APC 超家族氨基酸转运蛋白的功能和高分辨率
- 批准号:
7450594 - 财政年份:2008
- 资助金额:
$ 9.97万 - 项目类别:
Function and High-Resolution of an APC superfamily amino acid transporter
APC 超家族氨基酸转运蛋白的功能和高分辨率
- 批准号:
7571708 - 财政年份:2008
- 资助金额:
$ 9.97万 - 项目类别:
Function and Regulation of NKCC2 in the Mammalian Kidney
NKCC2 在哺乳动物肾脏中的功能和调节
- 批准号:
7499847 - 财政年份:2007
- 资助金额:
$ 9.97万 - 项目类别:
Mechanisms of Membrane Transport Gordon Conference 2003
膜传输机制戈登会议 2003
- 批准号:
6677730 - 财政年份:2003
- 资助金额:
$ 9.97万 - 项目类别:
FUNCTION AND REGULATION OF NKCC2 IN THE MAMMALIAN KIDNEY
NKCC2 在哺乳动物肾脏中的功能和调节
- 批准号:
6725895 - 财政年份:2003
- 资助金额:
$ 9.97万 - 项目类别:
NA+/K+/CL- AND K+/CL- COTRANSPORTERS IN MAMMALIAN KIDNEY
哺乳动物肾脏中的 NA /K /CL- 和 K /CL- 协同转运蛋白
- 批准号:
6574316 - 财政年份:2001
- 资助金额:
$ 9.97万 - 项目类别:
NA+/K+/CL- AND K+/CL- COTRANSPORTERS IN MAMMALIAN KIDNEY
哺乳动物肾脏中的 NA /K /CL- 和 K /CL- 协同转运蛋白
- 批准号:
6354687 - 财政年份:2000
- 资助金额:
$ 9.97万 - 项目类别:
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