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,并且是慢性炎症的中心介质。
炎症单核细胞被认为对动脉粥样硬化病变病理学有显著贡献。在
动脉粥样硬化病变,单核细胞/巨噬细胞已被证明表达脂质氧化
一种酶,15-脂氧合酶(15 LO),通过氧化
磷脂、胆固醇酯和游离脂肪酸。这种酶的独特产物是
氧化亚油酸酯(13-S-HPODE),我们已经证明这是主要的氧化脂肪酸,
大多数以酯化形式存在的动脉粥样硬化病变。正常单核细胞不表达15 LO,
但通过暴露于细胞因子IL-13诱导这种酶的表达,
与动脉粥样硬化动物模型中的疾病进展相关。第一次会议提出的研究报告
本申请的目的是鉴定新的IL-13触发的信号转导途径,
诱导15 LO基因在原代人单核细胞中表达,并将其与双重免疫应答相关。
磷酸化StatS,一个关键的转录因子调节15 LO。我们还将调查
StatS在15 LO特异性转录激活中的直接与间接作用。建议的研究
目的2将探讨以下假设:15 LO的诱导是许多细胞的关键调节步骤。
观察到调节清道夫受体CD 36表达的途径。其中的新奇
这些研究是通过使用以下方法阐明15 LO和CD 36途径的相互作用而得出的:
创新的方法,具体剖析这些途径在完整的,主要的人类
单核细胞这些包括我们小组发现单核细胞特别有利于
反义寡脱氧核糖核苷酸操纵特定的蛋白质表达,也由于最近的
这是一个突破,允许有效转染原代人单核细胞。我们还将定义
我们最近发现用氧化磷脂处理单核细胞
导致15 LO表达的显著抑制。选择氧化磷脂可能因此干扰
与动脉粥样硬化病变中脂氧合酶表达的关系。这些研究将大大提高
我们对15 LO表达所涉及的信号传导机制及其对免疫功能的影响的了解
CD 36的表达以及确定CD 36抑制15 LO表达的机制。
这些途径的调节将影响氧化磷脂、氧化胆固醇酯
和氧化脂肪酸以及调节损伤巨噬细胞泡沫细胞的形成和进展,
动脉粥样硬化病变15 LO和CD 36表达调控新途径的鉴定
可能会提出新的治疗方法,可用于干扰这一途径及其作用,
慢性炎症性疾病,如动脉粥样硬化。
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: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: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: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--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 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 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: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: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