Cholesterol modulation of BK currents and cerebral artery diameter via channel-forming slo1 subunits
胆固醇通过通道形成 slo1 亚基调节 BK 电流和脑动脉直径
基本信息
- 批准号:10751934
- 负责人:
- 金额:$ 3.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAlcoholsAllosteric RegulationAmino Acid SequenceAmino AcidsArteriesAtherosclerosisBindingBinding SitesBiochemicalBiological AssayBlood VesselsBlood flowBrainCalciumCellular MembraneCerebrovascular CirculationCerebrumCholesterolCognitive deficitsConsensusDataDementiaDialysis procedureDiameterElectrophysiology (science)EquilibriumFunctional disorderGoalsHomeostasisIndividualKnock-in MouseKnock-outKnowledgeLifeLigandsModernizationModificationMolecularMonitorMuscle CellsMuscle TonusNutrientOxygenPathologicPathologyPatternPhysiologicalPhysiologyPoint MutationProtein FamilyProtein IsoformsProteinsPublishingRecreationRegulationResistanceScanningSchemeSecondary toSite-Directed MutagenesisSmooth MuscleSterolsStrokeSystemic blood pressureTailTestingTimeTyrosineUnited StatesVascular Smooth MuscleVoltage-Gated Potassium Channelcerebral arterycerebrovascularcerebrovascular pathologydrug of abuseexperimental studyhypercholesterolemialarge-conductance calcium-activated potassium channelsmouse modelmutantnanoscalepatch clamppharmacologicrational designreceptorresponsewestern diet
项目摘要
Regulation of cerebral blood flow is necessary for survival as the brain requires a large amount of circulating
oxygen and nutrients. Resistance-size cerebral arteries manage constant blood flow to the brain by myogenic
autoregulation mechanisms. Abnormal cholesterol levels trigger dysregulation of resistance-size cerebral
arteries via the calcium- and voltage-gated potassium channel of large conductance (BK), contributing to
common cerebrovascular pathologies such as stroke, cognitive deficits including some forms of dementia, and
the disruption of cerebral artery function by recreational alcohol. Cholesterol inhibition of the BK channel alters
contractility of vascular smooth muscle impacting cerebral artery diameter, and dysregulates delivery of oxygen
and nutrients throughout the brain. While cholesterol diminishes BK channel activity, the molecular
mechanism(s) by which this occurs are currently unknown. Cholesterol recognition/interaction amino acid
consensus (CRAC) motifs are potential binding sites for cholesterol, and ten are found throughout the BK channel
amino acid sequence. The cytosolic tail domain contains seven of these ten CRAC motifs, and it has been
demonstrated that cholesterol modulates BK currents by one or more of these cytosolic tail domain CRAC motifs.
My goal is to determine the molecular mechanisms that govern cholesterol regulation of the BK channel by
interacting with certain cytosolic tail domain CRAC motif(s), and to define the impact of this regulation on cerebral
artery diameter. This proposal addresses two main aims: Aim 1 will determine the structural basis and gating
mechanisms that lead to cholesterol-induced hindering of BK function through cholesterol direct interactions with
the BK channel-forming slo1 subunit. The hypothesis that cholesterol modulates BK currents via interaction with
specific CRACs will be addressed by electrophysiology and binding experiments. I will also identify which BK
gating parameter(s) are altered upon cholesterol interaction. 1.1. I will first determine the contribution of distinct
CRAC motifs to cholesterol binding and the consequent inhibition of homomeric slo1 channel activity. 1.2. Next,
I will determine the critical physicochemical features of distinct CRAC motifs that allow for modulation of the
channel’s cholesterol sensitivity. 1.3. Finally, I will identify the cholesterol-sensitive gating parameters that lead
to cholesterol-induced hindering of slo1 channel activity. Aim 2 will address the physiological and
pharmacological consequences of cholesterol-slo1 interactions via CRAC4 motif as an example on native BKs
in cerebral artery smooth muscle and cerebral artery diameter. 2.1. I will determine the effects of cholesterol
interactions with CRAC4 in native BKs in arterial myocytes under physiological conditions. 2.2. I will also
determine the consequences of cholesterol regulation of BK currents via slo1 CRAC4 on artery diameter. This
proposal will for the first time develop a unifying scheme that explains the actions of cholesterol on BK channel
function and cerebral artery diameter at both molecular and cellular levels based on direct binding of the sterol
to the BK channel-forming slo1 subunit and/or allosteric regulation secondary to the sterol interaction.
由于大脑需要大量的循环,因此调节脑血流量对生存是必要的
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 }}
Elizabeth Hope Schneider其他文献
Elizabeth Hope Schneider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 }}
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 3.88万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 3.88万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 3.88万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 3.88万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 3.88万 - 项目类别:
Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 3.88万 - 项目类别:
Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
- 批准号:
10065645 - 财政年份:2023
- 资助金额:
$ 3.88万 - 项目类别:
Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 3.88万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 3.88万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 3.88万 - 项目类别:
Grant-in-Aid for Scientific Research (C)