Ca2+ waves in hepatocytes: Mechanisms and effects
Ca2+ waves in hepatocytes: Mechanisms and effects
批准号:
9902430
负责人:
MICHAEL H NATHANSON
金额:
$51.46万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-04-01 至 2023-03-31
关键词:
Animal ModelApicalBile fluidBindingBiologicalBiologyCalciumCalcium ChannelCalcium OscillationsCalcium SignalingCell modelChildhoodCholestasisCytosolDiseaseEndoplasmic ReticulumEpigenetic ProcessEpithelialEpitheliumEventGeneticHealthHepatocyteHumanImpairmentInositolLaboratoriesLiver diseasesMediatingMembraneMicroRNAsMolecularMolecular BiologyOrganic Anion TransportersPatientsPhysiologyPropertyProtein IsoformsRegulationRoleSignal TransductionTestingTherapeuticTranslatingWorkbile acid transportercholestatic liver diseaseclinically significantepigenetic regulationhistone methylationliver functionliver transplantationnew therapeutic targetnovel therapeuticsreceptortranscription factor
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Bile secretion is one of the principal functions of the liver. Cholestasis, or impaired bile flow, is a cardinal
manifestation of liver disease. Cholestatic liver diseases are an important group of disorders, which collectively
represent the most common indication for pediatric liver transplant and account for one in ten of all liver
transplants. This project investigates a basic biological mechanism in epithelial biology that is directly relevant
for the regulation of secretion in hepatocytes in health and disease. Calcium signals in hepatocytes are formed
largely by calcium release from the inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R), which is an InsP3-
gated calcium channel in the endoplasmic reticulum (ER). The type II InsP3R (InsP3R-2) is the predominant
isoform in hepatocytes, constituting 80% of the total pool of InsP3Rs, and is most concentrated in a specialized
region of the ER beneath the canalicular membrane. Calcium signals in hepatocytes generally begin as calcium
waves that originate in this region, and the apical pool of InsP3R-2 in hepatocytes is important for mediating
calcium waves and canalicular secretion. In contrast, the type I InsP3R (InsP3R-1), which constitutes the
remaining 20% of the InsP3R pool in hepatocytes, preferentially localizes to a different subcellular region and
does not affect secretion. The hypothesis of this project is that the factors that regulate the expression and
subcellular distribution of InsP3R-2 also regulate hepatocyte secretion, so that cholestasis is mediated by these
effects on InsP3R-2. In particular, we will test whether cholestatic liver diseases are due in part to impaired
expression and/or peri-canalicular targeting of InsP3R-2, which in turn impairs polarized calcium waves in the
cytosol and downstream events including regulation of the bile acid transporter Bsep and the organic anion
transporter Mrp2. This hypothesis will be tested through the following specific aims: (1) We will determine the
genetic and epigenetic factors that regulate expression of InsP3R-2 in hepatocytes. (2) We will determine the
molecular basis for, and cellular effects of, targeting InsP3R-2 to the ER-canalicular membrane interface. (3) We
will determine whether and how InsP3R-2 expression and/or pericanalicular targeting is impaired in hepatocytes
during canalicular cholestasis. We also will determine whether the efficacy of new therapies being developed
for treatment of cholestatis disorders is mediated in part by modulating InsP3R-2. Collectively, these studies will
break new ground in our understanding of the ways in which signaling microdomains are established in
hepatocytes, and have the potential to establish new paradigms for translating these observations into
understanding the mechanistic basis for a range of clinically significant human liver diseases.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Yale Liver Center
-
批准号:10388648
-
项目类别:
-
资助金额:$5.07万
-
财政年份:2021
-
负责人:MICHAEL H NATHANSON
-
依托单位:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
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批准号:10298412
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项目类别:
-
资助金额:$65.79万
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财政年份:2021
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负责人:MICHAEL H NATHANSON
-
依托单位:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
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批准号:10494268
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项目类别:
-
资助金额:$65.8万
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财政年份:2021
-
负责人:MICHAEL H NATHANSON
-
依托单位:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
-
批准号:10617893
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项目类别:
-
资助金额:$16.75万
-
财政年份:2021
-
负责人:MICHAEL H NATHANSON
-
依托单位:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
-
批准号:10646369
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项目类别:
-
资助金额:$64.88万
-
财政年份:2021
-
负责人:MICHAEL H NATHANSON
-
依托单位:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
-
批准号:10874892
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项目类别:
-
资助金额:$16.75万
-
财政年份:2021
-
负责人:MICHAEL H NATHANSON
-
依托单位:
Ca2+ waves in hepatocytes: Mechanisms and effects
-
批准号:10388244
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项目类别:
-
资助金额:$51.46万
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财政年份:2018
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负责人:MICHAEL H NATHANSON
-
依托单位:
Molecular regulation of cholestasis in cholangiocytes
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批准号:9925220
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项目类别:
-
资助金额:$47.89万
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财政年份:2018
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负责人:MICHAEL H NATHANSON
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依托单位:
Enrichment Program
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批准号:8916082
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项目类别:
-
资助金额:$59.01万
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财政年份:2015
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负责人:MICHAEL H NATHANSON
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依托单位:
Trafficking of the EGF receptor to the nucleus: Mechanisms and Effects
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批准号:8152910
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项目类别:
-
资助金额:$7.7万
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财政年份:2012
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负责人:MICHAEL H NATHANSON
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依托单位:
Trafficking of the EGF receptor to the nucleus: Mechanisms and Effects
-
批准号:8490515
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项目类别:
-
资助金额:$7.59万
-
财政年份:2012
-
负责人:MICHAEL H NATHANSON
-
依托单位:
Trafficking of the EGF receptor to the nucleus: Mechanisms and Effects
-
批准号:8607221
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项目类别:
-
资助金额:$7.75万
-
财政年份:2012
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负责人:MICHAEL H NATHANSON
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依托单位:
A laser scanning confocal microscope for research and education
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批准号:7838072
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项目类别:
-
资助金额:$93.12万
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财政年份:2010
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负责人:MICHAEL H NATHANSON
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依托单位:
A confocal endomicroscope for clinical research
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批准号:7791136
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项目类别:
-
资助金额:$15.99万
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财政年份:2010
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负责人:MICHAEL H NATHANSON
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依托单位:
Regulation of Liver by Nuclear Ca2+ Signaling
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批准号:7861351
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项目类别:
-
资助金额:$2.36万
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财政年份:2009
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负责人:MICHAEL H NATHANSON
-
依托单位:
Ca2+ Waves in Hepatocytes: Mechanisms and Effects
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批准号:7905575
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项目类别:
-
资助金额:$10.0万
-
财政年份:2009
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负责人:MICHAEL H NATHANSON
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依托单位:
Morphology Core
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批准号:7688377
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项目类别:
-
资助金额:$23.5万
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财政年份:2009
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负责人:MICHAEL H NATHANSON
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依托单位:
CELL IMAGING
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批准号:7424053
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项目类别:
-
资助金额:$11.78万
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财政年份:2007
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负责人:MICHAEL H NATHANSON
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依托单位:
Core--Administrative
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批准号:7500426
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项目类别:
-
资助金额:$15.54万
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财政年份:2007
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负责人:MICHAEL H NATHANSON
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依托单位:
REGULATION OF CELL GROWTH BY NUCLEAR CALCIUM
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批准号:7424049
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项目类别:
-
资助金额:$22.57万
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财政年份:2007
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负责人:MICHAEL H NATHANSON
-
依托单位:
国内基金
海外基金
FGF8通过Ras/MEK/ERK信号通路调控apical ES结构影响精子生成的机制研究
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批准号:81801519
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项目类别:青年科学基金项目
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资助金额:21.0万元
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批准年份:2018
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负责人:于岚
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依托单位: