Lysophosphatidic acid & tissue factor in atherosclerosis
溶血磷脂酸
基本信息
- 批准号:7062447
- 负责人:
- 金额:$ 24.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-07-01 至 2008-04-30
- 项目状态:已结题
- 来源:
- 关键词:G proteinRNA interferenceatherosclerosiscell surface receptorsenzyme linked immunosorbent assayfluorescence microscopygenetic regulationgenetically modified animalsimmunoprecipitationin situ hybridizationlaboratory mouselysolecithinspathologic processpolymerase chain reactionprotein isoformsprotein kinase Cscintillation counterthromboplastinwestern blottings
项目摘要
DESCRIPTION (provided by applicant): The long-term objective of this proposal is to explore the pathological role of LPA, a component of oxidized LDL, in atherosclerosis. The driving hypothesis of the proposal is that one of the mechanisms by which LPA, a component of oxLDL, contributes to atherosclerosis is via up-regulation of TF expression. This hypothesis is based on our novel findings that 1) lipid lysophosphatidic acid (LPA), which has recently been shown to accumulate in high concentrations in atherosclerotic lesions and identified as a component of oxLDL, markedly increases TF mRNA, TF protein production and TF activity in SMC; 2) LPA induced-TF gene expression requires the activation of a particular G-protein, MAPK, PKC, the novel protein kinase D (PKD), and ribosome S6 kinase (p90RSK); and 3) LPA induces TF mRNA expression in heart, kidney and aorta of the living animal. This hypothesis is also supported by the observations recently reported by others: 1) Tissue factor (TF) plays an important role in the development of atherosclerosis; 2) LPA accumulates in high concentrations in atherosclerotic lesions; and 3) LPA induces neointimal formation in rat aorta. This hypothesis is innovative because in the development of atherosclerosis, the role of this phospholipid LPA, which forms during oxidation of LDL and is secreted from activated platelets, is totally unknown. The goals of this proposal will be achieved through the following specific aims: Aim 1:To identify and determine the role of LPA receptor, specific G-protein, and the particular isoform of protein kinase C in LPA-stimulated TF expression, using specific antagonists of LPA receptors, affinity labeling, antisense oligonucleotides, as well as the dominant-negative approach. Aim 2: To explore the novel biological role of PKD and p90RSK in TF gene regulation, using selective inhibitors and the dominant-negative strategy. Aim 3: Using a well-established atherosclerotic model-ApoE knockout mouse, to determine i) the role of LPA in the development of atherosclerosis; ii) the role of TF in mediating the pathological effect of LPA in atherosclerotic lesion development in vivo.
The information obtained from the proposed studies may lead to the identification of novel therapeutic targets for the prevention and treatment of atherosclerosis. The proposed studies would also contribute to the understanding of the cellular signaling pathway that mediates the biological effects of LPA, specifically the effects on gene regulation in general. The proposed studies would also provide novel insight into the biological and cellular function of PKD and p90RSK in the vascular wall.
描述(申请人提供):这项提案的长期目标是探索LPA,氧化低密度脂蛋白的一种成分,在动脉粥样硬化中的病理作用。该提案的驱动假设是,oxLDL的一种成分LPA促进动脉粥样硬化的机制之一是通过上调TF的表达。这一假说基于我们的新发现:1)脂溶磷脂酸(LPA)最近被证明是oxLDL的一种成分,在动脉粥样硬化病变中高浓度积聚,显著增加SMC的TF mRNA、TF蛋白的产生和TF的活性;2)LPA诱导的TF基因表达需要激活特定的G蛋白,MAPK,PKC,新的蛋白激酶D(PKD)和核糖体S6激酶(P90RSK);以及3)LPA诱导活的动物的心脏、肾脏和主动脉的TF mRNA表达。这一假说也得到了最近报道的结果的支持:1)组织因子(TF)在动脉粥样硬化的发生发展中起重要作用;2)LPA在动脉粥样硬化病变中大量积聚;3)LPA诱导大鼠主动脉新生内膜形成。这一假说是创新的,因为在动脉粥样硬化的发展过程中,这种磷脂LPA的作用是完全未知的,这种磷脂LPA是在低密度脂蛋白氧化过程中形成的,由激活的血小板分泌。目的1:利用LPA受体的特异性拮抗剂、亲和标记、反义寡核苷酸以及显性-负性方法,鉴定和确定LPA受体、特异性G蛋白和蛋白激酶C的特殊异构体在LPA刺激的转铁蛋白表达中的作用。目的:利用选择性抑制剂和显性-负性策略,探讨PKD和p90RSK在TF基因调控中的新的生物学作用。目的:利用已建立的动脉粥样硬化模型--载脂蛋白E基因敲除小鼠,研究LPA在动脉粥样硬化形成中的作用,以及Tf在体内介导LPA在动脉粥样硬化病变发展中的病理作用。
从拟议的研究中获得的信息可能会导致确定预防和治疗动脉粥样硬化的新的治疗靶点。建议的研究也将有助于理解介导LPA生物学效应的细胞信号通路,特别是对基因调控的总体影响。拟议的研究也将为了解PKD和p90RSK在血管壁中的生物学和细胞功能提供新的见解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MEI-ZHEN CUI其他文献
MEI-ZHEN CUI的其他文献
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The Matricellular Protein Cyr61 Signaling Axis in Arterial Restenosis
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- 批准号:
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- 资助金额:
$ 24.74万 - 项目类别:
The Matricellular Protein Cyr61 Signaling Axis in Arterial Restenosis
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10647849 - 财政年份:2020
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$ 24.74万 - 项目类别:
The Matricellular Protein Cyr61 Signaling Axis in Arterial Restenosis
动脉再狭窄中的基质细胞蛋白 Cyr61 信号轴
- 批准号:
10192828 - 财政年份:2020
- 资助金额:
$ 24.74万 - 项目类别:
The Matricellular Protein Cyr61 Signaling Axis in Arterial Restenosis
动脉再狭窄中的基质细胞蛋白 Cyr61 信号轴
- 批准号:
10030144 - 财政年份:2020
- 资助金额:
$ 24.74万 - 项目类别:
Novel mechanism mediating LPA-induced smooth muscle cell and vascular responses
介导 LPA 诱导平滑肌细胞和血管反应的新机制
- 批准号:
9759964 - 财政年份:2018
- 资助金额:
$ 24.74万 - 项目类别:
Novel mechanism mediating LPA-induced smooth muscle cell and vascular responses
介导 LPA 诱导平滑肌细胞和血管反应的新机制
- 批准号:
8280311 - 财政年份:2011
- 资助金额:
$ 24.74万 - 项目类别:
Novel mechanism mediating LPA-induced smooth muscle cell and vascular responses
介导 LPA 诱导平滑肌细胞和血管反应的新机制
- 批准号:
8086122 - 财政年份:2011
- 资助金额:
$ 24.74万 - 项目类别:
Novel mechanism mediating LPA-induced smooth muscle cell and vascular responses
介导 LPA 诱导平滑肌细胞和血管反应的新机制
- 批准号:
8675918 - 财政年份:2011
- 资助金额:
$ 24.74万 - 项目类别:
Novel mechanism mediating LPA-induced smooth muscle cell and vascular responses
介导 LPA 诱导平滑肌细胞和血管反应的新机制
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9383988 - 财政年份:2011
- 资助金额:
$ 24.74万 - 项目类别:
Novel mechanism mediating LPA-induced smooth muscle cell and vascular responses
介导 LPA 诱导平滑肌细胞和血管反应的新机制
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8467042 - 财政年份:2011
- 资助金额:
$ 24.74万 - 项目类别:
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