ApoA1 lipidation by ABCA1 in HDL biogenesis
HDL 生物合成中 ABCA1 对 ApoA1 脂化
基本信息
- 批准号:10206232
- 负责人:
- 金额:$ 47.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:ATP binding cassette transporter 1Apolipoprotein A-IApolipoproteinsApolipoproteins BAreaAtherosclerosisBindingBiochemicalBiogenesisBiological AssayBiological MarkersBiologyCardiovascular DiseasesCell Membrane ProteinsCell membraneCell surfaceCellsCholesterolConsensusCoronary heart diseaseDataDetergentsDropsEndotheliumEnvironmentExcretory functionExtracellular DomainFutureGenerationsGenesGeneticGrantHigh Density Lipoprotein CholesterolHigh Density LipoproteinsHumanIntestinesKnowledgeLDL Cholesterol LipoproteinsLeadLigandsLipidsLipoproteinsLiposomesLiverLogistic RegressionsMeasuresMediatingMembraneMendelian randomizationMolecularMutagenesisObservational StudyPathway interactionsPeripheralPharmaceutical PreparationsPhosphatidylinositol 4,5-DiphosphatePhosphatidylinositolsPhosphatidylserinesPhospholipidsPlasmaPlayPredispositionProcessProductionProspective StudiesProteinsProton PumpRNAReactionReportingResearchResearch DesignRoleSteroid biosynthesisStructureSystemTangier DiseaseTertiary Protein StructureTestingTherapeuticTissuesTransgenic MiceTriglyceridescardiovascular disorder preventioncardiovascular disorder riskepidemiology studygenetic variantimmunoregulationinorganic phosphateinsightlipid metabolismmembrane activitymouse modelnovelparticlepopulation basedpreventprotective effectprotein protein interactionreconstitutionrecruitreverse cholesterol transporttumor progressionvacuolar H+-ATPase
项目摘要
High levels of high density lipoprotein-cholesterol (HDL-C) are associated with lowered risk for cardiovascular disease (CVD) in epidemiological studies. However, recent genetic and drug studies have shown that HDL-C itself is probably not causal in reducing CVD risk. Instead, a consensus is building that HDL functions may protect against CVD, and that treating for the biomarker of HDL-C may not always coincide with increased HDL function. One of the functions of HDL that may play a role in its protective effect is its role in the reverse cholesterol transport (RCT) pathway, in which cholesterol is removed from peripheral tissues and transferred to the liver for excretion. HDL and its major protein constituent, apolipoprotein-AI (apoA1), are critical components of this process. In the first step of the RCT pathway, lipid-poor apoA1 acts as an acceptor for cell cholesterol and phospholipids via the cell membrane protein ABCA1, generating nascent HDL through a mechanism which is not understood at the molecular level. ABCA1 has several well characterized activities, the outward translocation of phosphatidylserine, and the cell surface binding of its ligand apoA1. In the last cycle of this grant we characterized two novel activities of ABCA1, the outward translocation of phosphatidylinositol (4,5) bis-phosphate (PIP2) that is responsible for apoA1 binding to ABCA1 expressing cells, and the recruitment of the lysosomal vacuolar ATPase (V-ATPase) to the plasma membrane leading to local acidification of apoA1 that promotes its unfolding and HDL biogenesis. Building on these discoveries we propose to develop a cell-free ABCA1 reconstituted system, allowing a better understanding of the mechanism by which ABCA1 assembles nascent HDL. In Aim 2, we explore the mechanism by which ABCA1 recruits V- ATPase to the plasma membrane. Successful completion of the proposed studies will increase our knowledge of the mechanism of de novo HDL production, which may yield insights into new strategies to increase HDL biogenesis and HDL function, and aid in the prevention of CVD.
流行病学研究表明,高密度脂蛋白-胆固醇(HDL-C)水平高与心血管疾病(CVD)风险降低相关。然而,最近的基因和药物研究表明HDL-C本身可能不是降低心血管疾病风险的原因。相反,一种共识正在形成,即HDL的功能可以预防心血管疾病,并且治疗HDL- c的生物标志物可能并不总是与HDL功能的增加相一致。HDL可能发挥其保护作用的功能之一是其在胆固醇逆向转运(RCT)途径中的作用,在该途径中,胆固醇从外周组织移除并转移到肝脏排泄。HDL及其主要蛋白成分载脂蛋白ai (apoA1)是这一过程的关键组成部分。在RCT途径的第一步,脂质贫乏的apoA1通过细胞膜蛋白ABCA1作为细胞胆固醇和磷脂的受体,通过分子水平上尚不清楚的机制产生新生的HDL。ABCA1有几个很好的特征活性,磷脂酰丝氨酸的向外移位,以及它的配体apoA1的细胞表面结合。在本研究的最后一个周期中,我们描述了ABCA1的两种新活性,磷脂酰肌醇(4,5)二磷酸(PIP2)的向外易位,负责apoA1与ABCA1表达细胞的结合,以及溶酶体空泡atp酶(v - atp酶)向质膜的募集,导致apoA1的局部酸化,促进其展开和HDL的生物发生。在这些发现的基础上,我们建议开发一种无细胞的ABCA1重组系统,以便更好地了解ABCA1组装新生HDL的机制。在Aim 2中,我们探索ABCA1向质膜招募V- atp酶的机制。这些研究的成功完成将增加我们对新生HDL生成机制的认识,这可能会为增加HDL生物发生和HDL功能的新策略提供见解,并有助于预防心血管疾病。
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 }}
Jonathan D Smith其他文献
Similar promotion of Aβ1-42 fibrillogenesis by native apolipoprotein E ε3 and ε4 isoforms
- DOI:
10.1186/1742-2094-1-15 - 发表时间:
2004-08-16 - 期刊:
- 影响因子:10.100
- 作者:
David Sweeney;Ralph Martins;Harry LeVine;Jonathan D Smith;Sam Gandy - 通讯作者:
Sam Gandy
Jonathan D Smith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('Jonathan D Smith', 18)}}的其他基金
Project 1 - Genes to Function: Causal Genes and their Roles in Cardiomyocyte and Atrial Physiology
项目 1 - 发挥功能的基因:因果基因及其在心肌细胞和心房生理学中的作用
- 批准号:
10646358 - 财政年份:2022
- 资助金额:
$ 47.95万 - 项目类别:
Project 1 - Genes to Function: Causal Genes and their Roles in Cardiomyocyte and Atrial Physiology
项目 1 - 发挥功能的基因:因果基因及其在心肌细胞和心房生理学中的作用
- 批准号:
10410648 - 财政年份:2022
- 资助金额:
$ 47.95万 - 项目类别:
Genetic modifiers of atherosclerosis and macrophage phenotypes
动脉粥样硬化和巨噬细胞表型的遗传修饰
- 批准号:
10306932 - 财政年份:2021
- 资助金额:
$ 47.95万 - 项目类别:
Molecular Medicine Training Program at Cleveland Clinic/Case Western Reserve University
克利夫兰诊所/凯斯西储大学分子医学培训项目
- 批准号:
10426323 - 财政年份:2021
- 资助金额:
$ 47.95万 - 项目类别:
Molecular Medicine Training Program at Cleveland Clinic/Case Western Reserve University
克利夫兰诊所/凯斯西储大学分子医学培训项目
- 批准号:
10620326 - 财政年份:2021
- 资助金额:
$ 47.95万 - 项目类别:
Molecular Medicine Training Program at Cleveland Clinic/Case Western Reserve University
克利夫兰诊所/凯斯西储大学分子医学培训项目
- 批准号:
10268038 - 财政年份:2021
- 资助金额:
$ 47.95万 - 项目类别:
Genetic modifiers of atherosclerosis and macrophage phenotypes
动脉粥样硬化和巨噬细胞表型的遗传修饰
- 批准号:
10626053 - 财政年份:2021
- 资助金额:
$ 47.95万 - 项目类别:
Oxidant resistant apoA1 in reverse cholesterol transport, inflammation and atherosclerosis
抗氧化剂 apoA1 在逆转胆固醇转运、炎症和动脉粥样硬化中的作用
- 批准号:
9451333 - 财政年份:2016
- 资助金额:
$ 47.95万 - 项目类别:
Mechanism of ApoA1 Lipidation by ABCA1 in HDL biogenesis
HDL生物合成中ABCA1对ApoA1脂化的机制
- 批准号:
9102483 - 财政年份:2016
- 资助金额:
$ 47.95万 - 项目类别:
Oxidant resistant apoA1 in reverse cholesterol transport, inflammation and atherosclerosis
抗氧化剂 apoA1 在逆转胆固醇转运、炎症和动脉粥样硬化中的作用
- 批准号:
9173990 - 财政年份:2016
- 资助金额:
$ 47.95万 - 项目类别:
相似海外基金
Understanding the role of immune complexes between apolipoprotein A-I and IgG in atherosclerotic cardiovascular disease
了解载脂蛋白 A-I 和 IgG 之间的免疫复合物在动脉粥样硬化性心血管疾病中的作用
- 批准号:
10634607 - 财政年份:2020
- 资助金额:
$ 47.95万 - 项目类别:
Understanding the role of anti-apolipoprotein A-I antibodies in atherosclerotic cardiovascular disease
了解抗载脂蛋白 A-I 抗体在动脉粥样硬化性心血管疾病中的作用
- 批准号:
10112952 - 财政年份:2020
- 资助金额:
$ 47.95万 - 项目类别:
Understanding the role of immune complexes between apolipoprotein A-I and IgG in atherosclerotic cardiovascular disease
了解载脂蛋白 A-I 和 IgG 之间的免疫复合物在动脉粥样硬化性心血管疾病中的作用
- 批准号:
10431791 - 财政年份:2020
- 资助金额:
$ 47.95万 - 项目类别:
Understanding the role of anti-apolipoprotein A-I antibodies in atherosclerotic cardiovascular disease
了解抗载脂蛋白 A-I 抗体在动脉粥样硬化性心血管疾病中的作用
- 批准号:
10002615 - 财政年份:2019
- 资助金额:
$ 47.95万 - 项目类别:
Apolipoprotein A-I and apolipoprotein E4 in cerebrovascular health and Alzheimer's disease pathogenesis
载脂蛋白 A-I 和载脂蛋白 E4 在脑血管健康和阿尔茨海默病发病机制中的作用
- 批准号:
331360 - 财政年份:2014
- 资助金额:
$ 47.95万 - 项目类别:
Studentship Programs
Dysfunction of apolipoprotein A-I reabsorption in diabetic proximal tubule
糖尿病近曲小管载脂蛋白A-I重吸收功能障碍
- 批准号:
25860414 - 财政年份:2013
- 资助金额:
$ 47.95万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
New diagnostic and therapeutic strategies for atherosclerosis using newly developed apolipoprotein A-I mimetic peptide
使用新开发的载脂蛋白 A-I 模拟肽治疗动脉粥样硬化的新策略
- 批准号:
24591123 - 财政年份:2012
- 资助金额:
$ 47.95万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Impact of self-association on structure and function of apolipoprotein A-I
自缔合对载脂蛋白A-I结构和功能的影响
- 批准号:
8819561 - 财政年份:2012
- 资助金额:
$ 47.95万 - 项目类别:
Impact of self-association on structure and function of apolipoprotein A-I
自缔合对载脂蛋白A-I结构和功能的影响
- 批准号:
8274615 - 财政年份:2012
- 资助金额:
$ 47.95万 - 项目类别:
Impact of self-association on structure and function of apolipoprotein A-I
自缔合对载脂蛋白A-I结构和功能的影响
- 批准号:
8460476 - 财政年份:2012
- 资助金额:
$ 47.95万 - 项目类别: