Ecosanoids-Induced Vascular Growth During Injury
Ecosanoids-Induced Vascular Growth During Injury
批准号:
7008601
负责人:
KAFAIT U MALIK
金额:
$35.64万
依托单位国家:
美国
项目类别:
财政年份:
2005
资助国家:
美国
项目状态:
已结题
起止时间:
2005-01-01 至 2009-12-31
关键词:
JUN kinaseangiogenesisangiotensin IIarachidonateartery stenosiscardiovascular injurycell growth regulationcytochrome P450eicosanoid metabolismeicosanoidsepidermal growth factorgrowth factor receptorshypertrophykinase inhibitorlaboratory ratlipoxygenasemitogen activated protein kinasemyogenesisphospholipase A2protein kinase Cprotein tyrosine kinaseregenerationvascular endotheliumvascular smooth muscle
中文摘要
说明(申请人提供):AA代谢产物通过脂氧合酶(LO)主要是12(S)-羟基二十碳四烯酸(HETE)和细胞色素P450(20-HETE),途径,引起血管收缩,血管平滑肌细胞(VSMC)增殖和/或肥大。然而,这些AA代谢物在损伤过程中促进血管重塑的机制尚不清楚。我们的初步观察结果表明:(1)大鼠血管内皮细胞也表达非受体酪氨酸激酶(P72Syk),其活性可被AA及其代谢产物5(S)、12(S)、15(S)和20-HETE以及Ang II(引起AA释放)所激活;b)p38丝裂原活化蛋白激酶(MAPK)和PKZETA的抑制剂可抑制Ang II诱导的P72 Syk的激活;和d)Ang I诱导的损伤动脉新生内膜的形成被显性阴性的P72Syk所减弱,这使我们得出以下中心假设:AA及其代谢产物,主要是HETE,通过通过表皮生长因子受体(EGFR)激活p38MAPK和PKcheeta来激活P72Syk,从而促进新生内膜的形成和狭窄。为了验证这一假说,将考虑以下特定的目标:目的1.测定AA及其代谢产物和Ang II对VSMC中P72 Syk的表达和激活。目的2.探讨AA及其代谢产物与VSMC中ERK1/2、p38MAPK、JNK、PKCheta、EGFR和P72 Syk的关系。瞄准。3.探讨P72Syk在AA及其代谢物(HETE)诱导的大鼠颈动脉球囊损伤后新生内膜形成中的作用及Ang II在体内对新生内膜形成的影响。目的:探讨P72Syk在体外对AA、HETES和Ang II诱导的VSMC迁移、增殖、肥大和细胞外基质产生的影响。本研究将促进我们对损伤过程中血管重塑机制的认识,并为开发治疗血管再狭窄和动脉粥样硬化等血管疾病的新药物提供合理的途径。
英文摘要
DESCRIPTION (provided by applicant): AA metabolites derived via lipoxygenase (LO) mainly 12(S)-hydroxyeicosatetraenoic acid (HETE) and cytochrome P450 (CYP450) (20-HETE), pathways, cause vasoconstriction, vascular smooth muscle cell (VSMC) hyperplasia and/or hypertrophy. However, the mechanism by which these AA metabolites promote vascular remodeling during injury is not well understood. Our preliminary observations that a) spleen tyrosine kinase (p72Syk), a non-receptor tyrosine kinase, is also expressed in rat VSMC and it is activated by AA and its metabolites 5(S)-, 12(S)-, 15(S) and 20-HETE and also Ang II (which causes release of AA); b) inhibitors of p38 mitogen activated protein kinase (MAPK) and PKCzeta minimize Ang II-induced p72 Syk activation; c) AA and HETEs, like Ang II, promote neointima formation in balloon injured rat carotid artery; and d) Ang I induced neointima formation in the injured artery is attenuated by dominant negative p72 Syk have led us to the following central hypothesis: AA and its metabolites, mainly HETEs, promote neointima formation and stenosis by activating p72 Syk via activation of p38 MAPK and PKCzeta through the epidermal growth factor receptor (EGFR). To test this hypothesis, the following specific aims will be considered: Aim 1. To determine the expression and activation of p72 Syk by AA and its metabolite and Ang II in VSMC. Aim 2. To examine the relationship between AA and its metabolites and ERK1/2, p38MAPK, JNK, PKCzeta, EGFR and p72 Syk in VSMC. Aim. 3. To investigate the contribution of p72 Syk to neointima formation by AA and its metabolites (HETEs) and of Ang II to in vivo in balloon injured rat carotid artery. Aim 4. To determine the contribution of p72 Syk in vitro to VSMC-migration, proliferation, hypertrophy and extracellular matrix production in response to AA, HETEs, and Ang II. The proposed studies should advance our knowledge of the mechanism involved in vascular remodeling during injury and provide a rational approach for the development of novel agents for the treatment vascular diseases including restenosis and atherosclerosis.
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Ecosanoids-Induced Vascular Growth During Injury
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批准号:7162636
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项目类别:
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资助金额:$34.61万
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财政年份:2005
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负责人:KAFAIT U MALIK
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依托单位:
Eicosanoid-Induced Vascular Growth During Injury
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批准号:8775685
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项目类别:
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资助金额:$38.05万
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财政年份:2005
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负责人:KAFAIT U MALIK
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依托单位:
Eicosanoid-Induced Vascular Growth During Injury
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批准号:8583336
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项目类别:
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资助金额:$37.85万
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财政年份:2005
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负责人:KAFAIT U MALIK
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依托单位:
Ecosanoids-Induced Vascular Growth During Injury
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批准号:7333267
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项目类别:
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资助金额:$34.61万
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财政年份:2005
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负责人:KAFAIT U MALIK
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依托单位:
Ecosanoids-Induced Vascular Growth During Injury
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批准号:7541784
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项目类别:
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资助金额:$34.61万
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财政年份:2005
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负责人:KAFAIT U MALIK
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依托单位:
Eicosanoid-Induced Vascular Growth During Injury
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批准号:8389893
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项目类别:
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资助金额:$36.77万
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财政年份:2005
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负责人:KAFAIT U MALIK
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依托单位:
Ecosanoids-Induced Vascular Growth During Injury
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批准号:6858344
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项目类别:
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资助金额:$36.5万
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财政年份:2005
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负责人:KAFAIT U MALIK
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依托单位:
Eicosanoid-Induced Vascular Growth During Injury
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批准号:8238737
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项目类别:
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资助金额:$39.92万
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财政年份:2005
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负责人:KAFAIT U MALIK
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依托单位:
Lipid/Lipoprotein Metabolism and Cardiovascular Diseases
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批准号:6761851
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项目类别:
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资助金额:$29.09万
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财政年份:1988
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负责人:KAFAIT U MALIK
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依托单位:
Lipid/Lipoprotein Metabolism and Cardiovascular Diseases
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批准号:7225523
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项目类别:
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资助金额:$20.76万
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财政年份:1988
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负责人:KAFAIT U MALIK
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依托单位:
Lipid/Lipoprotein Metabolism and Cardiovascular Diseases
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批准号:6592951
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项目类别:
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资助金额:$27.04万
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财政年份:1988
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负责人:KAFAIT U MALIK
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依托单位:
Lipid/Lipoprotein Metabolism and Cardiovascular Diseases
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批准号:7034489
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项目类别:
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资助金额:$30.0万
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财政年份:1988
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负责人:KAFAIT U MALIK
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依托单位:
Lipid/Lipoprotein Metabolism and Cardiovascular Diseases
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批准号:6908240
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项目类别:
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资助金额:$7.56万
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财政年份:1988
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负责人:KAFAIT U MALIK
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依托单位:
Angiotensins, Prostaglandins-Adrenergic Interactions
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批准号:10176555
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项目类别:
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资助金额:$64.31万
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财政年份:1977
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负责人:KAFAIT U MALIK
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依托单位:
ANGIOTENSINS, PROSTAGLANDINS--ADRENERGIC INTERACTIONS
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批准号:2397027
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项目类别:
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资助金额:$33.97万
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财政年份:1977
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负责人:KAFAIT U MALIK
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依托单位:
ANGIOTENSINS, PROSTAGLANDINS--ADRENERGIC INTERACTIONS
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批准号:2771225
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项目类别:
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资助金额:$43.2万
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财政年份:1977
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负责人:KAFAIT U MALIK
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依托单位:
ANGIOTENSIN, PROSTAGLANDINS-ADRENERGIC INTERACTIONS
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批准号:3335752
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项目类别:
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资助金额:$21.27万
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财政年份:1977
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负责人:KAFAIT U MALIK
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依托单位:
ANGIOTENSINS PROSTAGLANDINS-ADRENERGIC INTERACTIONS
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批准号:3485612
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项目类别:
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资助金额:$29.06万
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财政年份:1977
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负责人:KAFAIT U MALIK
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依托单位:
ANGIOTENSINS PROSTAGLANDINS-ADRENERGIC INTERACTIONS
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批准号:3485619
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项目类别:
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资助金额:$27.24万
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财政年份:1977
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负责人:KAFAIT U MALIK
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依托单位:
Angiotensins, Prostaglandins-Adrenergic Interactions
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批准号:7466195
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项目类别:
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资助金额:$58.13万
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财政年份:1977
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负责人:KAFAIT U MALIK
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依托单位:
国内基金
海外基金
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