Mechanism of ApoA1 Lipidation by ABCA1 in HDL biogenesis
Mechanism of ApoA1 Lipidation by ABCA1 in HDL biogenesis
批准号:
9102483
负责人:
Jonathan D Smith
金额:
$40.76万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-04-01 至 2020-02-28
关键词:
ATP binding cassette transporter 1Apolipoprotein A-IApolipoproteins AApolipoproteins BAtherosclerosisBindingBiochemicalBiogenesisBiological AssayBiological MarkersCETP geneCardiovascular DiseasesCell Membrane ProteinsCell membraneCell surfaceCellsCholesterolClinicalConsensusCoronary heart diseaseDataDependenceDevelopmentEpidemiologic StudiesExcretory functionFailureFutureGeneticHigh Density Lipoprotein CholesterolHigh Density LipoproteinsHumanIncidenceKnowledgeLeadLigandsLipidsLiverMediatingMembrane ProteinsModelingMolecularMutationN-terminalNicotinic AcidsPathway interactionsPeripheralPharmaceutical PreparationsPharmacotherapyPhosphatidylinositol 4,5-DiphosphatePhosphatidylinositol PhosphatesPhosphatidylinositolsPhosphatidylserinesPhospholipidsPlayProcessProductionProteinsProton PumpRandomizedReactionResistanceRiskRoleSerumSignal TransductionSiteStructureTestingTherapeuticTissuesbasebiophysical analysiscardiovascular disorder preventioncardiovascular disorder riskcrosslinkgenetic variantinhibitor/antagonistinsightmouse modelnovelnovel therapeuticsoverexpressionpreventprotective effectpublic health relevancereverse cholesterol transportstoichiometrytranslocasevacuolar H+-ATPase
中文摘要
英文摘要
DESCRIPTION (provided by applicant): 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 A-I (apoA-I), are critical components of this process. In the first ste of the RCT pathway, lipid-poor apoA-I 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 two well characterized activities, the outward translocation of phosphatidylserine, and the cell surface binding of its ligand apoA-I. We recently
characterized a third activity of ABCA1, the ability to unfold apoA-I's N-terminal helical hairpin.In Aim 1, we explore our novel finding that phosphatidylinositol phosphates (PIPs) play a role in nascent HDL biogenesis. In Aim 2, we explore the mechanism by which ABCA1 helps partially unfold apoA-I on the cell surface, including the role of our novel finding of ABCA1 mediated acidification of apoA-I on the cell surface. 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.
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会议论文
Project 1 - Genes to Function: Causal Genes and their Roles in Cardiomyocyte and Atrial Physiology
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批准号:10646358
-
项目类别:
-
资助金额:$50.72万
-
财政年份:2022
-
负责人:Jonathan D Smith
-
依托单位:
Project 1 - Genes to Function: Causal Genes and their Roles in Cardiomyocyte and Atrial Physiology
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批准号:10410648
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项目类别:
-
资助金额:$50.72万
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财政年份:2022
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负责人:Jonathan D Smith
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依托单位:
Genetic modifiers of atherosclerosis and macrophage phenotypes
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批准号:10306932
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项目类别:
-
资助金额:$63.26万
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财政年份:2021
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负责人:Jonathan D Smith
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依托单位:
Molecular Medicine Training Program at Cleveland Clinic/Case Western Reserve University
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批准号:10426323
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项目类别:
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资助金额:$31.22万
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财政年份:2021
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负责人:Jonathan D Smith
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依托单位:
Molecular Medicine Training Program at Cleveland Clinic/Case Western Reserve University
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批准号:10268038
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项目类别:
-
资助金额:$29.26万
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财政年份:2021
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负责人:Jonathan D Smith
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依托单位:
Molecular Medicine Training Program at Cleveland Clinic/Case Western Reserve University
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批准号:10620326
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项目类别:
-
资助金额:$31.83万
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财政年份:2021
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负责人:Jonathan D Smith
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依托单位:
Genetic modifiers of atherosclerosis and macrophage phenotypes
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批准号:10626053
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项目类别:
-
资助金额:$61.88万
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财政年份:2021
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负责人:Jonathan D Smith
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依托单位:
Oxidant resistant apoA1 in reverse cholesterol transport, inflammation and atherosclerosis
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批准号:9451333
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项目类别:
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资助金额:$39.63万
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财政年份:2016
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负责人:Jonathan D Smith
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依托单位:
Oxidant resistant apoA1 in reverse cholesterol transport, inflammation and atherosclerosis
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批准号:9173990
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项目类别:
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资助金额:$39.63万
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财政年份:2016
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负责人:Jonathan D Smith
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依托单位:
ApoA1 lipidation by ABCA1 in HDL biogenesis
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批准号:10206232
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项目类别:
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资助金额:$47.95万
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财政年份:2016
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负责人:Jonathan D Smith
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依托单位:
Oxidant resistant apoA1 in reverse cholesterol transport, inflammation and atherosclerosis
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批准号:9276118
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项目类别:
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资助金额:$39.63万
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财政年份:2016
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负责人:Jonathan D Smith
-
依托单位:
ApoA1 lipidation by ABCA1 in HDL biogenesis
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批准号:10642780
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项目类别:
-
资助金额:$47.95万
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财政年份:2016
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负责人:Jonathan D Smith
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依托单位:
Atherosclerosis and Lipoprotein Analysis Core
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批准号:8242737
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项目类别:
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资助金额:$26.11万
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财政年份:2011
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负责人:Jonathan D Smith
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依托单位:
Characterization of Atherosclerosis Modifier Genes
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批准号:8131145
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项目类别:
-
资助金额:$46.65万
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财政年份:2010
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负责人:Jonathan D Smith
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依托单位:
Characterization of Atherosclerosis Modifier Genes
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批准号:8280217
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项目类别:
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资助金额:$46.66万
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财政年份:2010
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负责人:Jonathan D Smith
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依托单位:
Characterization of Atherosclerosis Modifier Genes
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批准号:8490709
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项目类别:
-
资助金额:$44.42万
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财政年份:2010
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负责人:Jonathan D Smith
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依托单位:
Characterization of Atherosclerosis Modifier Genes
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批准号:7983316
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项目类别:
-
资助金额:$46.57万
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财政年份:2010
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负责人:Jonathan D Smith
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依托单位:
ABCA1, ApoAI and Reverse Cholesterol Transport
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批准号:8015694
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项目类别:
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资助金额:$51.26万
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财政年份:2010
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负责人:Jonathan D Smith
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依托单位:
Atherosclerosis and Lipoprotein Analysis Core
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批准号:7659846
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项目类别:
-
资助金额:$10.82万
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财政年份:2009
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负责人:Jonathan D Smith
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依托单位:
Genetics of Atherosclerosis in a Murine Model
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批准号:7786022
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项目类别:
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资助金额:$48.83万
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财政年份:2009
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负责人:Jonathan D Smith
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依托单位:
海外基金