Role of PKCbeta in Diet-induced Hypercholesterolemia
PKCbeta 在饮食引起的高胆固醇血症中的作用
基本信息
- 批准号:7326829
- 负责人:
- 金额:$ 28.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-12-06 至 2009-07-14
- 项目状态:已结题
- 来源:
- 关键词:ATP-Binding Cassette TransportersAbbreviationsAffectAffinityAgingAmericanAmino AcidsAnabolismAnimalsApolipoprotein EApolipoproteinsArtsAtherosclerosisAttentionBindingBinding ProteinsBinding SitesBiochemicalBiological AssayCaloriesCause of DeathCell physiologyCholesterolCholesterol HomeostasisComplementComplexCoronary ArteriosclerosisCyclodextrinsDietDietary CholesterolDietary FatsDoctor of PhilosophyEndoplasmic ReticulumEnvironmentExtracellular Signal Regulated KinasesFamilyFatty acid glycerol estersFigs - dietaryGene ExpressionGenesGeneticGoalsGolgi ApparatusHepaticHepatocyteHigh Density LipoproteinsHumanHypersensitivityIndividualInvestigationKnock-outKnowledgeLDL Cholesterol LipoproteinsLigandsLinkLipidsLipoproteinsLiverLow Density Lipoprotein ReceptorLow-Density LipoproteinsMAP Kinase GeneMAPK14 geneMEKKsMEKsMass Spectrum AnalysisMeasuresMediatingMembraneMinkMitogen-Activated Protein KinasesMitogensMixed Function OxygenasesModificationMolecularMolecular BiologyMusMutant Strains MiceNaturePhenotypePhosphorylationPhosphotransferasesPhysiologicalPhysiologyPlasmaPopulationPreventiveProcessPropertyProtein BindingProtein IsoformsProtein KinaseProtein Kinase CProtein OverexpressionProteinsProteolysisProteolytic ProcessingRateRegulationRegulator GenesResponse ElementsRisk FactorsRoleSerumSignal PathwaySignal TransductionSignal Transduction PathwaySocietiesSqualene SynthetaseSterolsStressStructureTechniquesTimeTransgenic MiceTransgenic OrganismsTwin StudiesWorkbasecholesterol absorptioncitrate carrierdaydensitydietary excessdisabilitydisorder preventionfeedinggain of functiongenetic linkage analysishuman MAP3K1 proteinhypercholesterolemiai-cholesterollipid disorderloss of functionmutantprotein kinase C betareceptorreceptor expressionresponsesaturated fatsensorsite-1 proteasetooltranscription factor
项目摘要
DESCRIPTION (provided by applicant): Coronary artery disease (CAD) remains the leading cause of death and disability in our society. Of all known risk factors promoting CAD, a high serum level of low-density lipoprotein (LDL)-cholesterol is one of the most important risk factors. The plasma level of this lipoprotein is strongly influenced by genetic factors and the amount of dietary fat and cholesterol; dietary modification remains the cornerstone of CAD prevention. Our knowledge of the regulatory mechanism(s) controlling cholesterol homeostasis in response to dietary cholesterol is limited, as is the role of signaling pathways initiated by alterations in cholesterol levels. Also, the interrelationships between these signaling pathways and sterol response element-binding proteins (SREBPs), as well as the mechanism linking SREBP processing and cholesterol levels are not clear. The emerging picture from our work is that regulation of hepatic LDL receptors, crucial for cholesterol homeostasis, results from the activity of a few interlinked regulatory signaling pathways. We have previously shown, for the first-time, involvement of specific isoforms of protein kinase C (PKC) in the regulation of LDL receptor expression in cultured hepatic cells, possibly through direct modulation of activity by cholesterol. Based on our recent results, we propose a central role for B-isoform of PKC (PKCb) in regulating cholesterol homeostasis via modulating expression of selected genes crucial for this process. In Specific Aim 1, the role of PKCb in cholesterol homeostasis will be established by evaluating the effect of knockout of this ldnase on overall cholesterol homeostasis. Initial studies with PKC(-deficient mice strongly support a central role of this kinase in controlling the responsiveness of plasma cholesterol to the changes in the dietary cholesterol content. Cholesterol metabolism will be compared in detail between normal and PKCb mutants fed special diets. The Specific Aim 2 will compare expression of the hepatic genes critical for cholesterol homeostasis in the above animals. In Specific Aim 3, mechanisms by which PKCb affects SREBP-2 expression and its proteolytic processing, possibly by regulating INSIG- 1 phosphorylation will be examined. Finally, the nature of the isoform-specific interaction between cholesterol and PKCb will be examined in the Specific Aim 4. The photoactive cholesterol probe will be used to define at the molecular level structure(s) and amino acids that produce isoform-specific binding of PKCb to cholesterol. The proposed studies will not only establish the role of PKCb in diet-induced hypercholesterolemia, but will also identify genes regulated by this kinase, to correlate regulatory mechanisms to animal physiology. They will also help understand the complex interactions between environment and genetics leading to atherosclerosis. Accomplishment of the above aims will unravel a central signaling component that may act as a sensor to respond to dietary cholesterol; modulation of its activity may be the preferable mode for the treatment of lipid disorders in the 21st century.
描述(由申请人提供):冠状动脉疾病(CAD)仍然是我们社会中死亡和残疾的主要原因。在所有已知的促进CAD的危险因素中,高血清水平的低密度脂蛋白(LDL)-胆固醇是最重要的危险因素之一。这种脂蛋白的血浆水平受到遗传因素和膳食脂肪和胆固醇量的强烈影响;饮食调整仍然是预防CAD的基石。我们对控制胆固醇稳态的调节机制的了解有限,因为胆固醇水平的改变引发的信号通路的作用也是有限的。此外,这些信号通路和固醇反应元件结合蛋白(SREBP)之间的相互关系,以及连接SREBP加工和胆固醇水平的机制尚不清楚。从我们的工作中出现的画面是,肝脏LDL受体的调节,胆固醇稳态的关键,结果从一些相互关联的调节信号通路的活动。我们以前已经表明,第一次,参与特定的蛋白激酶C(PKC)的异构体在培养的肝细胞中的LDL受体表达的调节,可能通过胆固醇的活性直接调制。基于我们最近的研究结果,我们提出了一个核心作用,B-亚型的PKC(PKC b)在调节胆固醇稳态通过调节表达的选定基因的这一过程中至关重要。在具体目标1中,将通过评估敲除该ldnase对总体胆固醇稳态的影响来确定PKCb在胆固醇稳态中的作用。对PKC β缺陷小鼠的初步研究强烈支持这种激酶在控制血浆胆固醇对饮食胆固醇含量变化的反应性中的中心作用。胆固醇代谢将详细比较正常和PKCb突变体之间的特殊饮食喂养。具体目标2将比较上述动物中对胆固醇稳态至关重要的肝脏基因的表达。在具体目标3中,将检查PKCb可能通过调节INSIG- 1磷酸化影响SREBP-2表达及其蛋白水解加工的机制。最后,胆固醇和PKCb之间的亚型特异性相互作用的性质将在具体目标4中进行检查。光敏胆固醇探针将用于在分子水平上确定产生PKCb与胆固醇的亚型特异性结合的结构和氨基酸。拟议的研究不仅将确定PKCb在饮食诱导的高胆固醇血症中的作用,而且还将确定由这种激酶调节的基因,以将调节机制与动物生理学相关联。他们还将有助于了解导致动脉粥样硬化的环境和遗传之间的复杂相互作用。上述目标的实现将解开一个中央信号组件,可以作为一个传感器,以响应饮食中的胆固醇;其活动的调制可能是在21世纪的脂质紊乱的治疗的优选模式世纪。
项目成果
期刊论文数量(0)
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KAMAL D MEHTA其他文献
KAMAL D MEHTA的其他文献
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{{ truncateString('KAMAL D MEHTA', 18)}}的其他基金
PKCbeta mediates dietary fat/cholesterol-induced cholesterol homeostasis
PKCbeta 介导膳食脂肪/胆固醇诱导的胆固醇稳态
- 批准号:
9368518 - 财政年份:2017
- 资助金额:
$ 28.35万 - 项目类别:
Role of PKCbeta in Diet-induced Hypercholesterolemia
PKCbeta 在饮食引起的高胆固醇血症中的作用
- 批准号:
7150032 - 财政年份:2004
- 资助金额:
$ 28.35万 - 项目类别:
Role of PKCbeta in Diet-induced Hypercholesterolemia
PKCbeta 在饮食引起的高胆固醇血症中的作用
- 批准号:
6857486 - 财政年份:2004
- 资助金额:
$ 28.35万 - 项目类别:
Role of PKCbeta in Diet-induced Hypercholesterolemia
PKCbeta 在饮食引起的高胆固醇血症中的作用
- 批准号:
6987879 - 财政年份:2004
- 资助金额:
$ 28.35万 - 项目类别:
Molecular Mechanism of Protein Kinase Cbeta-Mediated Cholesterol Homeostasis
蛋白激酶Cbeta介导的胆固醇稳态的分子机制
- 批准号:
7894724 - 财政年份:2004
- 资助金额:
$ 28.35万 - 项目类别:
Molecular Mechanism of Protein Kinase Cbeta-Mediated Cholesterol Homeostasis
蛋白激酶Cbeta介导的胆固醇稳态的分子机制
- 批准号:
7653553 - 财政年份:2004
- 资助金额:
$ 28.35万 - 项目类别:
Mechanisms of p42/44MAPK-induced LDL receptor expression
p42/44MAPK诱导LDL受体表达的机制
- 批准号:
6573814 - 财政年份:2001
- 资助金额:
$ 28.35万 - 项目类别:
Mechanisms of p42/44MAPK-induced LDL receptor expression
p42/44MAPK诱导LDL受体表达的机制
- 批准号:
6656862 - 财政年份:2001
- 资助金额:
$ 28.35万 - 项目类别:
Mechanisms of p42/44MAPK-induced LDL receptor expression
p42/44MAPK诱导LDL受体表达的机制
- 批准号:
6537871 - 财政年份:2001
- 资助金额:
$ 28.35万 - 项目类别:
Mechanisms of p42/44MAPK-induced LDL receptor expression
p42/44MAPK诱导LDL受体表达的机制
- 批准号:
6773909 - 财政年份:2001
- 资助金额:
$ 28.35万 - 项目类别:
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