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发生得更早,且在有代谢的患者中更为严重
综合征和2型糖尿病。心脏病是糖尿病患者的主要死因。这个
胰岛素抵抗和高血糖促进动脉粥样硬化的机制尚不清楚,也不清楚
这些代谢异常促进动脉粥样硬化形成的部位已知。PI已经发展成
组织特异性胰岛素抵抗模型,并建立了胰岛素调节的信号级联
通过叉头转录因子FoxO1进行基因表达。拟议的PPG是一个理想的场地
将PI在胰岛素作用和胰岛素抵抗模型方面的经验与Tall的专业知识相结合
和Tabas实验室在肝脂蛋白周转、巨噬细胞生物学和
动脉硬化。该项目有两个具体目标:目标1将研究FoxO1依赖的机制
肝内致动脉粥样硬化性血脂异常。PI将检验肝脏胰岛素抵抗通过
Foxo1可促进致动脉粥样硬化的脂质成分,增加极低密度脂蛋白ApoB的分泌。建议数
实验将研究FoxOI依赖的转录增加对甘油三酯合成的影响,
FFA氧化和脂蛋白周转。体内研究将探讨FoxOI是否可以调节
动脉粥样硬化的易感性和高血糖对FoxOI活性的影响。Aim 2将考察该角色
FoxO1/3在巨噬细胞胆固醇负荷诱导未折叠蛋白反应(UPR)中的作用
胆固醇负荷和SRA结扎诱导巨噬细胞UPR。正如Tall博士的初步研究显示的那样
而Tabas,巨噬细胞中的胰岛素抵抗增加了对胆固醇诱导的细胞凋亡的敏感性。
这一过程与CD36、SRA和CHOP表达增加以及AKT和AKT减少有关。
FOXO磷酸化。PI将产生FoxO1/3缺陷的巨噬细胞,以检测改变的效果
FoxOI/3在胆固醇诱导的UPR和动脉粥样硬化中的表达PI将使用RNA分析
FoxOI/3缺失的巨噬细胞映射FoxO转录靶点并将此信息与
巨噬细胞FoxO1/3在Tabas和Tall项目中的功能分析这些措施的结果是
研究旨在为胰岛素抵抗和高脂血症的治疗提供新的途径。
以肝脏和巨噬细胞FoxO活性调节为基础的2型糖尿病。
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
-
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
-
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
-
批准号:7500522
-
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
-
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:
Diabetes and Endocrinology Research Center
-
批准号:6740820
-
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:
MECHANISMS OF BETA CELL FAILURE
-
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:
海外基金