Ileal Bile Acid Transporter Metabolism and Regulation
回肠胆汁酸转运蛋白代谢和调节
基本信息
- 批准号:7223479
- 负责人:
- 金额:$ 22.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1994
- 资助国家:美国
- 起止时间:1994-05-10 至 2010-03-31
- 项目状态:已结题
- 来源:
- 关键词:ApicalAppearanceBackBile AcidsBindingBiological AssayCaco-2 CellsCellsConditionDevelopmentDietary FatsDiseaseEnd PointEnterocytesEnterohepatic CirculationEpithelial CellsExcretory functionGene TargetingGenesGoalsIn VitroIntestinesKnock-outKnockout MiceMDCK cellMembrane Transport ProteinsMessenger RNAMetabolismModelingMolecularMusOrphanPhysiologicalPropertyProteinsProximal Kidney TubulesRangeRateRegulationRelative (related person)RoleTestingThinkingTissuesTranscriptional RegulationTransmembrane TransportWorkabsorptionbasolateral membranebile acid transporterbrush border membranecholangiocytefeedingin vivolipid metabolismmouse modelprogramspromotersizetranscription factoruptake
项目摘要
DESCRIPTION (provided by applicant): Many of the major carriers responsible for the enterohepatic circulation have been identified in recent years. Notably absent from that list is the basolateral membrane transporter responsible for the efflux of bile acids from the ileal enterocyte, renal proximal tubule cell, and cholangiocyte. This has hindered understanding the molecular mechanism and regulation of bile acid flux through the enterohepatic circulation. We have recently applied a gene profiling approach to the ileal bile acid transporter knockout mouse in order to identify a candidate basolateral bile acid transporter, Osta/b. The goal of the proposed work is to test the hypothesis that Osta/b is the major ileal basolateral bile acid transporter and to understand its regulation. To accomplish these goals, three specific aims are proposed. Aim 1: To test the hypothesis that the heteromeric Osta/b transporter is an ileal basolateral bile acid transporter. For this aim, the following questions will be investigated. 1) What tissues express Osta/b mRNA and protein? 2) What is the cellular localization of the Osta/b protein? 3) Does Osta/b promote bile acid efflux in transfected MDCK cells, a model polarized epithelial cell? 4) Does Osta/b expression correlate with the appearance of transcellular bile acid flux in intestinal development and in Caco-2 cells programmed to differentiate? 5) Is Osta/b expression necessary for basolateral membrane transport in Caco-2 cells, a model intestinal polarized epithelial cell? Aim 2: To use knockout mouse models to determine the relative contribution of Osta/b to intestinal bile acid transport. For this study, bile acid metabolism including fecal bile acid excretion, bile acid pool size, and intestinal bile acid absorption will be examined in Mrp3 and Osta null mice. Aim 3: To elucidate the mechanism responsible for bile acid regulation of the ileal Osta/b. The goal of this aim is to elucidate the transcriptional mechanisms responsible for the regulation of the Osta and Ostb genes by bile acids. For this aim, the regulation of mouse Osta/b by bile acid feeding or depletion will be investigated in vivo. The transcriptional regulation of the Osta gene will be investigated in vitro using transfected promoter constructs and transcription factor binding assays. The long-range goal of this work is to understand the mechanism and regulation of ileal bile acid transport as it relates to dietary lipid metabolism in normal and disease states.
描述(由申请人提供):近年来,许多负责肠-肝循环的主要载体已被确定。值得注意的是,基侧膜转运体负责从回肠肠上皮细胞、肾近端小管细胞和胆管细胞中流出胆汁酸。这阻碍了对胆汁酸通过肠-肝循环流动的分子机制和调节的了解。我们最近将基因图谱方法应用于回肠胆汁酸转运体基因敲除小鼠,以确定候选的基底外侧胆汁酸转运体Osta/b。拟议工作的目的是检验Osta/b是主要的回肠基底外侧胆汁酸转运体的假设,并了解其调控。为了实现这些目标,提出了三个具体目标。目的1:验证异构体Osta/b转运蛋白是回肠基底外侧胆汁酸转运蛋白的假说。为此,将调查以下问题。1)哪些组织表达Osta/b的mRNA和蛋白?2)Osta/b蛋白在细胞中的定位是什么?3)Osta/b是否促进了模型极化上皮细胞MDCK细胞的胆汁酸外流?4)Osta/b的表达是否与肠道发育和Caco-2细胞中跨细胞胆酸通量的出现有关?5)Osta/b的表达对模型肠道极化上皮细胞Caco-2的基侧膜转运是必需的吗?目的:利用基因敲除小鼠模型,确定OstA/b在肠道胆汁酸转运中的相对作用。在这项研究中,将检测MRP3和OSTA缺失小鼠的胆汁酸代谢,包括粪便胆汁酸排泄、胆酸池大小和肠道胆汁酸吸收。目的3:阐明胆汁酸对回肠OstA/b基因的调控机制,旨在阐明胆汁酸调控Osta和Ostb基因的转录机制。为此,将在体内研究胆汁酸摄入或耗尽对小鼠OstA/b的调节。OSTA基因的转录调控将通过转基因启动子构建和转录因子结合试验在体外进行研究。这项工作的长期目标是了解回肠胆汁酸转运的机制和调节,因为它与正常和疾病状态下的饮食脂肪代谢有关。
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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PAUL A DAWSON其他文献
PAUL A DAWSON的其他文献
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{{ truncateString('PAUL A DAWSON', 18)}}的其他基金
Host-Microbial Control of Deoxycholate Producton
脱氧胆酸生产的宿主微生物控制
- 批准号:
6944397 - 财政年份:2004
- 资助金额:
$ 22.31万 - 项目类别:
Host-Microbial Control of Deoxycholate Producton
脱氧胆酸生产的宿主微生物控制
- 批准号:
6804278 - 财政年份:2004
- 资助金额:
$ 22.31万 - 项目类别:
Ileal Bile Acid Transporter Metabolism and Regulation
回肠胆汁酸转运蛋白代谢和调节
- 批准号:
7391628 - 财政年份:1994
- 资助金额:
$ 22.31万 - 项目类别:
Ileal Bile Acid Transporter Metabolism and Regulation
回肠胆汁酸转运蛋白代谢和调节
- 批准号:
9982316 - 财政年份:1994
- 资助金额:
$ 22.31万 - 项目类别:
ILEAL BILE ACID TRANSPORTER METABOLISM AND REGULATION
回肠胆汁酸转运蛋白的代谢和调节
- 批准号:
2147973 - 财政年份:1994
- 资助金额:
$ 22.31万 - 项目类别:
ILEAL BILE ACID TRANSPORTER METABOLISM AND REGULATION
回肠胆汁酸转运蛋白的代谢和调节
- 批准号:
2414867 - 财政年份:1994
- 资助金额:
$ 22.31万 - 项目类别:
Ileal Bile Acid Transporter Metabolism and Regulation
回肠胆汁酸转运蛋白代谢和调节
- 批准号:
7057736 - 财政年份:1994
- 资助金额:
$ 22.31万 - 项目类别:
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