Atherogenic Patheways Mediated by FOXO
Atherogenic Patheways Mediated by FOXO
批准号:
7329717
负责人:
DOMENICO ACCILI
金额:
$55.45万
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-07-01 至 2012-06-30
关键词:
1-Phosphatidylinositol 3-KinaseAbbreviationsAcetylationAddressAdipocytesAffectApolipoproteins BApoptosisAtherosclerosisBindingCD36 geneCardiovascular DiseasesCause of DeathCholesterolDataDeacetylaseDevelopmentDiabetes MellitusDyslipidemiasFamilyGene ExpressionGene Expression RegulationGenetic TranscriptionGlucoseHeart DiseasesHepaticHistonesHyperglycemiaIndividualInduction of ApoptosisInsulinInsulin ReceptorInsulin ResistanceInvestigationKnock-in MouseKupffer CellsLaboratoriesLigationLinkLipidsLipoproteinsLiverLow Density Lipoprotein ReceptorMacrophage Cell BiologyMapsMediatingMetabolicMetabolic syndromeMetabolismModelingModificationMusMutationNon-Insulin-Dependent Diabetes MellitusOrganPAWR proteinPatientsPhosphorylationPositioning AttributePredispositionProcessPropertyProtein-Serine-Threonine KinasesProteinsProto-Oncogene Proteins c-aktProto-OncogenesPyruvatePyruvatesRNARegulatory ElementRoleSignal TransductionSiteSterolsStressTailTestingTissue ModelTissuesTriglyceridesVery low density lipoproteinatherogenesisbasecell typedeprivationdiabeticexperienceforkhead proteinin vivoinorganic phosphateinterestlifetime risklipid metabolismloss of functionmacrophagemutantnovel strategiesoxidationresearch studyresponse
中文摘要
动脉粥样硬化及其并发症在代谢紊乱的患者中发生得更早、更严重
英文摘要
Atherosclerosis and its complications occur earlier and are more severe in patients with the metabolic
syndrome and type 2 diabetes. Heart disease is the leading cause of death among diabetics. The
mechanisms by which insulin resistance and hyperglycemia accelerate atherosclerosis are not clear, nor are
the sites at which these metabolic abnormalities promote atherogenesis known. The PI has developed
models of tissue-specific insulin resistance and established a signaling cascade by which insulin regulates
gene expression via the forkhead transcription factor FoxO1. The proposed PPG represents an ideal venue
to integrate the Pi's experience in insulin action and models of insulin resistance with the expertise of the Tall
and Tabas laboratories in studies of hepatic lipoprotein turnover, macrophage cell biology and
atherosclerosis. This project has two Specific Aims: Aim 1 will investigate mechanism of FoxO1-dependent
atherogenic dyslipidemia in liver. The PI will test the hypothesis that hepatic insulin resistance acts through
FoxO1 to promote an atherogenic lipid profile, with increased VLDL ApoB secretion. The proposed
experiments will investigate the effects of increased FoxOI-dependent transcription on triglyceride synthesis,
FFA oxidation and lipoprotein turnover. In vivo studies will address whether FoxOI can modulate the
susceptibilty to atherosclerosis and the role of hyperglycemia on FoxOI activity. Aim 2 will examine the role
of FoxO1/3 in the induction of Unfolded Protein Response (UPR) by cholesterol loading of macrophages.
Cholesterol loading and SRA ligation induce macrophage UPR. As shown in preliminary studies by Drs. Tall
and Tabas, insulin resistance in the macrophage increases susceptibility to cholesterol-induced apoptosis.
This process is associated with increased CD36, SRA and CHOP expression, as well as decreased AKT and
FoxO phosphorylation. The PI will generate FoxO1/3-deficient macrophages to examine the effect of altered
FoxOI/3 expression on cholesterol-induced UPR and atherosclerosis. The PI will use RNA profiling of
FoxOI/3-deficient macrophage to map the FoxO transcriptional targets and integrate this information with
the functional analysis of macrophage FoxO1/3 in the Tabas and Tall projects. The upshot of these
investigations is to provide new approaches to the therapy of lipid abnormalities in insulin resistance and
type 2 diabetes based on the modulation of FoxO activity in liver and macrophages.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mouse Models of Insulin Resistance
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批准号:10617186
-
项目类别:
-
资助金额:$49.0万
-
财政年份:2020
-
负责人:DOMENICO ACCILI
-
依托单位:
Mouse Models of Insulin Resistance
-
批准号:10207591
-
项目类别:
-
资助金额:$49.0万
-
财政年份:2020
-
负责人:DOMENICO ACCILI
-
依托单位:
Mouse Models of Insulin Resistance
-
批准号:10395560
-
项目类别:
-
资助金额:$49.0万
-
财政年份:2020
-
负责人:DOMENICO ACCILI
-
依托单位:
Mouse Models of Insulin Resistance
-
批准号:10057493
-
项目类别:
-
资助金额:$49.0万
-
财政年份:2020
-
负责人:DOMENICO ACCILI
-
依托单位:
MOUSE MODELS OF INSULIN RESISTANCE
-
批准号:9045751
-
项目类别:
-
资助金额:$42.5万
-
财政年份:2015
-
负责人:DOMENICO ACCILI
-
依托单位:
Diabetes and Endocrinology Research Center
-
批准号:8063347
-
项目类别:
-
资助金额:$6.45万
-
财政年份:2010
-
负责人:DOMENICO ACCILI
-
依托单位:
Insulin Resistance in Vascular Endothelial Cells and Foxo
-
批准号:8460254
-
项目类别:
-
资助金额:$54.01万
-
财政年份:2007
-
负责人:DOMENICO ACCILI
-
依托单位:
PPAR-gamma Deacetylation in Cardiometabolic Disease
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批准号:10428379
-
项目类别:
-
资助金额:$54.68万
-
财政年份:2007
-
负责人:DOMENICO ACCILI
-
依托单位:
Islet and Immunology
-
批准号:7500528
-
项目类别:
-
资助金额:$12.51万
-
财政年份:2007
-
负责人:DOMENICO ACCILI
-
依托单位:
PPAR-gamma Deacetylation in Cardiometabolic Disease
-
批准号:10197191
-
项目类别:
-
资助金额:$54.68万
-
财政年份:2007
-
负责人:DOMENICO ACCILI
-
依托单位:
Admin Core
-
批准号:7509429
-
项目类别:
-
资助金额:$20.47万
-
财政年份:2007
-
负责人:DOMENICO ACCILI
-
依托单位:
Protein Production Core
-
批准号:7500526
-
项目类别:
-
资助金额:$11.02万
-
财政年份:2007
-
负责人:DOMENICO ACCILI
-
依托单位:
Hormone & Metabolites
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批准号:7500522
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项目类别:
-
资助金额:$15.18万
-
财政年份:2007
-
负责人:DOMENICO ACCILI
-
依托单位:
Genomics Core
-
批准号:7500521
-
项目类别:
-
资助金额:$16.52万
-
财政年份:2007
-
负责人:DOMENICO ACCILI
-
依托单位:
Pilot and Feasibility
-
批准号:7500533
-
项目类别:
-
资助金额:$24.23万
-
财政年份:2007
-
负责人:DOMENICO ACCILI
-
依托单位:
Animal Phenotyping
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批准号:7500530
-
项目类别:
-
资助金额:$15.57万
-
财政年份:2007
-
负责人:DOMENICO ACCILI
-
依托单位:
Insulin Resistance in Vascular Endothelial Cells and Foxo
-
批准号:8996692
-
项目类别:
-
资助金额:$54.01万
-
财政年份:2007
-
负责人:DOMENICO ACCILI
-
依托单位:
Insulin Resistance in Vascular Endothelial Cells and Foxo
-
批准号:8606763
-
项目类别:
-
资助金额:$52.93万
-
财政年份:2007
-
负责人:DOMENICO ACCILI
-
依托单位:
MECHANISMS OF BETA CELL FAILURE
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批准号:6672380
-
项目类别:
-
资助金额:$40.26万
-
财政年份:2003
-
负责人:DOMENICO ACCILI
-
依托单位:
Diabetes and Endocrinology Research Center
-
批准号:6848675
-
项目类别:
-
资助金额:$122.63万
-
财政年份:2003
-
负责人:DOMENICO ACCILI
-
依托单位:
海外基金