Calcium Dynamics in Interstitial Cells of Cajal
Cajal 间质细胞中的钙动态
基本信息
- 批准号:10425251
- 负责人:
- 金额:$ 35.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-04-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressBicarbonatesBindingCalciumCellsComplexConstipationDataDiseaseElectrophysiology (science)EnteralEpigenetic ProcessExonsFrequenciesGLI Family ProteinGastrointestinal MotilityGastrointestinal TransitGastrointestinal tract structureGastroparesisGenesGeneticGenetic TranscriptionGrantHealthHumanImmune systemInterstitial Cell of CajalIntestinesIon ChannelIonsIrritable Bowel SyndromeKnockout MiceLinkMeasurementMediatingMethodsMicroscopyMusMuscleNerveNervous system structureNeurogliaPacemakersPatternPharmacologyPhysiologicalPlayPredispositionPropertyPublishingRegulationResolutionRoleSeriesSingle Nucleotide PolymorphismSmall IntestinesSmooth MuscleSpeedTechniquesTestingTranscription Initiation SiteTranscriptional RegulationUp-RegulationVariantWild Type MouseWorkZinc Fingersbasecell motilitycell typedensitydifferential expressionexperimental studyextracellulargastrointestinalinnovationmotility disordermouse modelnovelpreventpromotersymporter
项目摘要
PROJECT SUMMARY/ABSTRACT
The extrinsic nervous system, enteric nerves, glia, the immune system, interstitial cells of Cajal (ICC) and
smooth muscle all need to work in concert to enable coordinated motility. The Ca2+ activated Cl- channel, Ano1
is expressed in ICC and is required for ICC electrical activity. In the previous grant cycles it was shown that
Ano1 regulates proliferation of ICC, that loss of Ano1 is associated with GI motility disorders, that spontaneous
Ca2+ transients in the myenteric ICC network are usually coordinated but are altered and highly uncoordinated
in Ano1 knockout mice, and the promoter for Ano1 was identified. How Ano1 regulates Ca2+ transients and
how Ano1 is regulated is not known but what is known, though underappreciated, is that Ano1 also conducts
HCO3-. The overarching novel hypothesis for this competitive renewal is that Ano1, acting with the
transporter Slc4a4, regulates ICC Ca2+ transients that in turn regulate electrical activity and that
transcriptional regulation of Ano1 levels in ICC by the zinc finger protein Gli physiologically regulates
contractile activity. The hypothesis will be tested in two specific aims (SA). SA1 will determine how
pacemaker function in myenteric ICC is regulated by pH through transport of bicarbonate ions by Ano1 and
Slc4a4 (NBCe1) and SA2 will determine how transcriptional regulation of Ano1 expression by Gli contributes to
normal intestinal pacemaking and GI motility. The SAs are supported by extensive preliminary data. 1)
Changing extracellular HCO3- alters intracellular Ca2+ transients but not when Ano1 is blocked; 2) Pacemaker
ICC differentially express the electrogenic Na+,HCO3- co-transporter Slc4a4 (NBCe1) variant c; 3) Genetic and
pharmacologic block of Ano1 and Slc4a4 alter intracellular Ca2+ transients through entry of HCO3- and
modulation of pH; 4) Gli1 and Gli2 bind directly to the promoter of Ano1; 5) Ano1 expression is inversely
correlated with Gli levels; 6) Inhibition of Gli markedly increases Ano1 currents; 7) Upregulation of Gli alters
downstream smooth muscle electrical activity, contractile patterns and GI transit; and 8) A single nucleotide
variant prevents Gli binding to the Ano1 promoter and is linked to susceptibility to irritable bowel syndrome
(IBS). To address the overarching hypothesis a variety of methods will be used, spanning from the use of
genetically encoded indicator molecules, high speed and high resolution microscopy techniques, intracellular
pH measurement, several genetically modified mouse models, electrophysiology, and improvements in the
ability to obtain genetic and epigenetic sequencing information from well identified cells. Additional new
expertise in genetics, transcriptional regulation, epigenetics and pH regulation has been integrated with the
established team to take an innovative approach to understanding GI pacemaking in health and disease. As a
result of previous work, the preliminary data, and the proposed experiments, a significant advance in the
understanding of the regulation of Ano1 and how Ano1 regulates Ca2+ transients will be achieved with
implications in both health and disease within and outside the GI tract.
项目总结/文摘
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
GIANRICO FARRUGIA其他文献
GIANRICO FARRUGIA的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('GIANRICO FARRUGIA', 18)}}的其他基金
CALCIUM DYNAMICS IN INTERSTITIAL CELLS OF CAJAL
CAJAL 间质细胞中的钙动力学
- 批准号:
6381720 - 财政年份:2000
- 资助金额:
$ 35.78万 - 项目类别:
Calcium Dynamics in Interstitial Cells of Cajal
Cajal 间质细胞中的钙动态
- 批准号:
8290442 - 财政年份:2000
- 资助金额:
$ 35.78万 - 项目类别:
CALCIUM DYNAMICS IN INTERSTITIAL CELLS OF CAJAL
CAJAL 间质细胞中的钙动力学
- 批准号:
6727510 - 财政年份:2000
- 资助金额:
$ 35.78万 - 项目类别:
Calcium Dynamics in Interstitial Cells of Cajal
Cajal 间质细胞中的钙动态
- 批准号:
7643917 - 财政年份:2000
- 资助金额:
$ 35.78万 - 项目类别:
Calcium Dynamics in Interstitial Cells of Cajal
Cajal 间质细胞中的钙动态
- 批准号:
8063209 - 财政年份:2000
- 资助金额:
$ 35.78万 - 项目类别:
相似海外基金
Studies of Aqueous Carbonates-Bicarbonates; Interactions of Ions in Natural Water Modeling (Chemistry)
含水碳酸盐-碳酸氢盐的研究;
- 批准号:
8406557 - 财政年份:1984
- 资助金额:
$ 35.78万 - 项目类别:
Continuing Grant














{{item.name}}会员




