Cholesterol regulation of smooth muscle BK channel proteins and consequent control of cerebral artery diameter
胆固醇对平滑肌 BK 通道蛋白的调节以及随后对脑动脉直径的控制
基本信息
- 批准号:10063416
- 负责人:
- 金额:$ 64.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAmino AcidsAnimal ModelAnteriorArteriesArteriosclerosisAtherosclerosisBindingBiological AssayBlood VesselsBrainBrain regionCalciumCaliberCell membraneCell modelCellsCerebrovascular CirculationCerebrovascular DisordersCerebrumChemosensitizationCholesterolCognitive deficitsComplementary DNAComputer ModelsConsensusCouplingDataDeformityDementiaDiseaseElectrophysiology (science)ElectroporationEndotheliumEngineeringEnsureFunctional disorderHigh PrevalenceIn VitroIncidenceInflammatoryIon ChannelKnowledgeLeadLinkLipid BilayersLipidsMass Spectrum AnalysisMediatingMethodsMicrocirculationMicrovascular DysfunctionModificationMolecularMorphologyMusMuscle ContractionMuscle TonusMuscle relaxation phaseMutateOrganPathologicPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhenotypePhysiologicalPhysiologyPotassiumPotassium ChannelPropertyProteinsRed CrossRegulationResistanceRisk FactorsRoleSarcoplasmic ReticulumScanningSecondary toSmooth MuscleSmooth Muscle MyocytesStrokeStructureTailTestingTherapeutic AgentsTissuesVasodilationVasodilator AgentsVoltage-Gated Potassium Channelanimal databasecerebral arterycholesterol controlconfocal imagingconstrictiondesignhemodynamicshuman datain vivointracranial arterylarge-conductance calcium-activated potassium channelsmiddle cerebral arterynovelparenchymal arteriolespatch clampstroke patienttraffickingvascular factorvoltage
项目摘要
Human and animal data demonstrate that cholesterol (CLR) may disrupt the smooth muscle (SM) tone of
resistance-size cerebral arteries in absence of any sign of arteriosclerosis or anatomical abnormalities, this CLR
action contributing to a vascular component of stroke. In a further step, stroke patients with dysfunction of large
cerebral arteries and high CLR will present a higher prevalence of arteriosclerosis. CLR actions on cerebral
artery SM tone have been attributed to endothelial, microcirculation, inflammatory and other circulating factors.
Departing from this current paradigm and supported by preliminary data, our central hypothesis is that CLR may
control resistance-size, cerebral artery SM tone and diameter via regulation of calcium- and voltage-gated
potassium channels of big conductance (BK) located in the cerebral artery SM plasmalemma. Here, BK function
primarily results from the coupling of channel-forming α (cbv1) and regulatory β1 subunits. The concerted action
of cbv1+β1 and eventual BK activation generates outward potassium current that opposes depolarization-
mediated calcium influx, limits SM contraction and favors artery dilation. Based on preliminary data, we predict
that under low β1 expression, CLR interaction (through direct binding and allosteric modulation) with selected
Cholesterol Recognition Amino acid Consensus motifs (CRACs) identified in the cbv1 cytosolic domain will lead
to CLR-induced reduction of BK current, SM contraction and cerebral artery constriction. In contrast, under high
β1 levels, CLR-driven increases in the plasmalemmal fraction of β1 and cbv1-β1 functional coupling will prevail,
leading to increased BK current, SM relaxation and artery dilation. We predict that brain arteries that differ in β1
expression will display a differential vulnerability to CLR, and that CLR levels in SM will condition the efficacy of
β1-dependent vasodilators. Our predictions will be tested along three specific aims (SA). SA1 (molecular level):
determine the structural bases and gating mechanisms that lead to CLR-induced hindering of BK (cbv1
homotetramer) function through CLR-cbv1 CRAC interactions. SA2 (cellular level): determine the mechanisms
that underlie CLR activation of cbv1+β1 channels. Knowledge from SA1 and SA2 will be integrated in SA3 (organ
level): determine the consequences of CLR-BK subunit interactions on the function of native BKs in cerebral
artery SM and on artery diameter under physiological conditions using in vitro and in vivo CLR delivery methods.
We combine unique expertise in computational modeling, binding assays, mass spectroscopy, differential
scanning fluorimetry, patch-clamp and lipid bilayer electrophysiology, allosteric gating analysis, electroporation
of SM cells and cerebral arteries from engineered mice with mutated cDNAs, subunit trafficking, confocal imaging
and cerebral artery diameter determinations, ensuring feasibility. We expect to challenge the paradigm that CLR
modulation of BK is secondary to nonspecific perturbation of bilayer physico-chemical properties, and to provide
milestone information on CLR control of cerebral artery function, which will be necessary to design small drugs
that adjust BK channel function to variable CLR levels and counteract CLR-associated cerebrovascular disease.
人类和动物的数据表明,胆固醇(CLR)可能会破坏平滑肌(SM)张力
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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Anna Bukiya其他文献
Anna Bukiya的其他文献
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{{ truncateString('Anna Bukiya', 18)}}的其他基金
Fetal cerebral arteries and prenatal alcohol exposure
胎儿脑动脉和产前酒精暴露
- 批准号:
10337722 - 财政年份:2022
- 资助金额:
$ 64.6万 - 项目类别:
Ionic mechanisms of toluene cerebrovascular actions
甲苯脑血管作用的离子机制
- 批准号:
10627927 - 财政年份:2022
- 资助金额:
$ 64.6万 - 项目类别:
Ionic mechanisms of toluene cerebrovascular actions
甲苯脑血管作用的离子机制
- 批准号:
10434289 - 财政年份:2022
- 资助金额:
$ 64.6万 - 项目类别:
Fetal cerebral arteries and prenatal alcohol exposure
胎儿脑动脉和产前酒精暴露
- 批准号:
10590708 - 财政年份:2022
- 资助金额:
$ 64.6万 - 项目类别:
Fetal alcohol exposure and cerebrovascular development
胎儿酒精暴露与脑血管发育
- 批准号:
10582618 - 财政年份:2021
- 资助金额:
$ 64.6万 - 项目类别:
Fetal alcohol exposure and cerebrovascular development
胎儿酒精暴露与脑血管发育
- 批准号:
10359771 - 财政年份:2021
- 资助金额:
$ 64.6万 - 项目类别:
Cholesterol regulation of smooth muscle BK channel proteins and consequent control of cerebral artery diameter
胆固醇对平滑肌 BK 通道蛋白的调节以及随后对脑动脉直径的控制
- 批准号:
10627854 - 财政年份:2020
- 资助金额:
$ 64.6万 - 项目类别:
Cholesterol regulation of smooth muscle BK channel proteins and consequent control of cerebral artery diameter
胆固醇对平滑肌 BK 通道蛋白的调节以及随后对脑动脉直径的控制
- 批准号:
10413935 - 财政年份:2020
- 资助金额:
$ 64.6万 - 项目类别:
Fetal cerebrovascular eCB system as a target of maternal alcohol consumption
胎儿脑血管eCB系统作为母体饮酒的目标
- 批准号:
8570401 - 财政年份:2014
- 资助金额:
$ 64.6万 - 项目类别:
Role of BK subunits in ethanol-cholesterol synergistic inhibition of BK channel
BK亚基在乙醇-胆固醇协同抑制BK通道中的作用
- 批准号:
8146995 - 财政年份:2010
- 资助金额:
$ 64.6万 - 项目类别:
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