REGULATION OF MONOCYTE 15-LIPOXYGENASE EXPRESSION
REGULATION OF MONOCYTE 15-LIPOXYGENASE EXPRESSION
批准号:
7337247
负责人:
Martha K Cathcart
金额:
$38.37万
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 2012-04-30
关键词:
13-hydroperoxy-9,11-octadecadienoic acidAnimal ModelAntisense OligodeoxyribonucleotidesArachidonate 15-LipoxygenaseAreaArterial Fatty StreakAtherosclerosisCD36 geneCell LineCellsChemical StructureCholesterol EstersChronicCollaborationsComplexDependenceDiseaseDisease ProgressionEnzymesEventExposure toFatty AcidsFoam CellsGene ExpressionGene Expression RegulationHumanInflammationInflammatoryInflammatory ResponseInterleukin-13InvestigationLaboratoriesLesionLigandsLinoleic AcidsLipidsLiposomesLipoxygenaseLocalizedLow Density Lipoprotein oxidationMediatingMediator of activation proteinModificationMusNonesterified Fatty AcidsNuclear ReceptorsNuclear TranslocationParticipantPathologyPathway interactionsPhospholipidsPhosphorylationPrincipal InvestigatorProcessProductionProtein OverexpressionProtocols documentationPublishingRegulationReportingRoleSignal TransductionSignal Transduction PathwayStructureTranscriptional ActivationTransfectionatherogenesiscell typecytokineinnovationinterleukin-13 receptormacrophagemonocytenoveloxidationoxidized lipidoxidized phosphatidyl cholinepreferencepromoterprotein expressionreceptorscavenger receptorsrc-Family Kinasestranscription factoruptake
中文摘要
单核细胞是炎症反应的主要参与者,也是慢性疾病的中心介质
英文摘要
Monocytes are major participants in inflammatory responses and are central mediators of chronic
inflammation. Monocytes are believed to significantly contribute to atherosclerotic lesion pathology. In
atherosclerotic lesions, monocyte/macrophages have been shown to expressthe lipid-oxidizing
enzyme, 15-lipoxygenase (15LO) that produces potent inflammatory mediators by oxidizing
phospholipids, cholesterol esters and free fatty acids. Unique among the products of this enzyme are
oxidized linoleate (13-S-HPODE), which we have shown to be the major oxidized fatty acid in
atherosclerotic lesions with most present in esterified form. Normal monocytes do not express 15LO,
but are induced to do so by exposure to the cytokine IL-13 and expression of this enzyme has been
correlated with disease progression in animal models of atherosclerosis. Studies proposed in the first
aim of this application will identify novel IL-13-triggered signal transduction pathways responsible for
inducing 15LO gene expression in primary human monocytes and relate them to the dual
phosphorylation of StatS, a critical transcription factor regulating 15LO. We will also investigate the
direct versus indirect role of StatS in specific transcriptional activation of 15LO. The studies proposed in
Aim 2 will explore the hypothesis that the induction of 15LO is a critical regulatory step for many of the
pathways observed to regulate the expression of the scavenger receptor CD36. The novelty of these
studies is derived from elucidating the interaction of the 15LO and CD36 pathways through the use of
innovative approaches to specifically dissect the roles of these pathways in intact, primary human
monocytes. These include the discovery by our group that monocytes are particularly conducive to
antisense oligodeoxyribonucleotide manipulation of specific protein expression and also due to a recent
breakthrough allowing efficient transfection of primary human monocytes. We will also define the
mechanisms involved in our recent finding that treatment of monocytes with oxidized phospholipids
causes dramatic inhibition of 15LO expression. Select oxidized phospholipids may thereforeinterfere
with the lipoxygenase expression in atherosclerotic lesions. These studies will substantially enhance
our understanding of the signaling mechanisms involved in the expression of 15LO and their impact on
the expression of CD36 as well as defining the mechanism of CD36 inhibition of 15LO expression.
Modulation of these pathways will impact formation of oxidized phospholipids, oxidized cholesterol ester
and oxidized fatty acids as well as modulate lesion macrophage foam cell formation and progression of
atherosclerotic lesions. The identification of new pathways that regulate 15LO and CD36 expression
will likely suggest novel therapies that may be employed to interfere with this pathway and its role in
chronic inflammatory disease such as atherosclerosis.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Molecular Medicine Training Program
-
批准号:8077520
-
项目类别:
-
资助金额:$8.84万
-
财政年份:2011
-
负责人:Martha K Cathcart
-
依托单位:
2009 Atherosclerosis Gordon Research Conference
-
批准号:7669740
-
项目类别:
-
资助金额:$1.5万
-
财政年份:2009
-
负责人:Martha K Cathcart
-
依托单位:
Vascular Biology and Medicine 2005/NAVBO Annual Meetings
-
批准号:7000802
-
项目类别:
-
资助金额:$1.5万
-
财政年份:2005
-
负责人:Martha K Cathcart
-
依托单位:
Vascular Biology and Medicine 2005 and NAVBO Annual Meetings
-
批准号:7108610
-
项目类别:
-
资助金额:$1.5万
-
财政年份:2005
-
负责人:Martha K Cathcart
-
依托单位:
PHOSPHOLIPASE REGULATION OF MONOCYTE CHEMOTAXIS TO MCP-1
-
批准号:6767717
-
项目类别:
-
资助金额:$34.43万
-
财政年份:2003
-
负责人:Martha K Cathcart
-
依托单位:
PHOSPHOLIPASE REGULATION OF MONOCYTE CHEMOTAXIS TO MCP-1
-
批准号:7077721
-
项目类别:
-
资助金额:$33.62万
-
财政年份:2003
-
负责人:Martha K Cathcart
-
依托单位:
PHOSPHOLIPASE REGULATION OF MONOCYTE CHEMOTAXIS TO MCP-1
-
批准号:6905681
-
项目类别:
-
资助金额:$34.43万
-
财政年份:2003
-
负责人:Martha K Cathcart
-
依托单位:
PHOSPHOLIPASE REGULATION OF MONOCYTE CHEMOTAXIS TO MCP-1
-
批准号:6674594
-
项目类别:
-
资助金额:$34.43万
-
财政年份:2003
-
负责人:Martha K Cathcart
-
依托单位:
MONOCYTE PATHOGENESIS--RESPIRATORY BURST OXIDASE
-
批准号:6527587
-
项目类别:
-
资助金额:$26.57万
-
财政年份:1999
-
负责人:Martha K Cathcart
-
依托单位:
MONOCYTE PATHOGENESIS--RESPIRATORY BURST OXIDASE
-
批准号:2766775
-
项目类别:
-
资助金额:$24.73万
-
财政年份:1999
-
负责人:Martha K Cathcart
-
依托单位:
MONOCYTE PATHOGENESIS--RESPIRATORY BURST OXIDASE
-
批准号:6390222
-
项目类别:
-
资助金额:$25.79万
-
财政年份:1999
-
负责人:Martha K Cathcart
-
依托单位:
Monocyte Pathogenesis: Regulation of NADPH Oxidase
-
批准号:6875800
-
项目类别:
-
资助金额:$34.43万
-
财政年份:1999
-
负责人:Martha K Cathcart
-
依托单位:
Monocyte Pathogenesis: Regulation of NADPH Oxidase
-
批准号:7221891
-
项目类别:
-
资助金额:$32.64万
-
财政年份:1999
-
负责人:Martha K Cathcart
-
依托单位:
Monocyte Pathogenesis: Regulation of NADPH Oxidase
-
批准号:6772279
-
项目类别:
-
资助金额:$34.43万
-
财政年份:1999
-
负责人:Martha K Cathcart
-
依托单位:
Monocyte Pathogenesis: Regulation of NADPH Oxidase
-
批准号:7050571
-
项目类别:
-
资助金额:$33.62万
-
财政年份:1999
-
负责人:Martha K Cathcart
-
依托单位:
MONOCYTE PATHOGENESIS--RESPIRATORY BURST OXIDASE
-
批准号:6184578
-
项目类别:
-
资助金额:$25.36万
-
财政年份:1999
-
负责人:Martha K Cathcart
-
依托单位:
MONOCYTE OXIDATION OF LIPOPROTEIN LIPIDS
-
批准号:2415611
-
项目类别:
-
资助金额:$19.83万
-
财政年份:1995
-
负责人:Martha K Cathcart
-
依托单位:
MONOCYTE OXIDATION OF LIPOPROTEIN LIPIDS
-
批准号:2702233
-
项目类别:
-
资助金额:$23.3万
-
财政年份:1995
-
负责人:Martha K Cathcart
-
依托单位:
INTERLEUKIN 13 STIMULATION OF HUMAN MONOCYTES
-
批准号:6389312
-
项目类别:
-
资助金额:$25.93万
-
财政年份:1995
-
负责人:Martha K Cathcart
-
依托单位:
MONOCYTE OXIDATION OF LIPOPROTEIN LIPIDS
-
批准号:2227475
-
项目类别:
-
资助金额:$19.07万
-
财政年份:1995
-
负责人:Martha K Cathcart
-
依托单位:
海外基金