MECHANISMS OF CARDIOVASCULAR DISEASE IN OBESITY

肥胖引起的心血管疾病的机制

基本信息

  • 批准号:
    6537360
  • 负责人:
  • 金额:
    $ 42.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1999
  • 资助国家:
    美国
  • 起止时间:
    1999-06-01 至 2004-05-31
  • 项目状态:
    已结题

项目摘要

Little information is available about the molecular mechanisms that promote the hypercoagulable state and increased risk for cardiovascular disease in human obesity. Although plasminogen activator inhibitor 1 (PAI-1) is consistently and significantly elevated in the plasma of obese humans and is a known risk factor for atherothrombolic disease, the origin and regulatory mechanism(s) that control its expression in obesity remain to be defined. Our studies of obese mice and cultured adipocytes suggest that elevated plasma PAI-1 results from increased synthesis by adipocytes in response to tumor necrosis factor-alpha and insulin, and that the adipocyte may play a central and previously unrecognized role in hemostatic gene expression in human obesity. The following observations provide additional novel insights into adipocytes and PAI-1 biosynthesis in obesity and form the basis of this application: (1) transforming growth factor beta (TGF-beta) mRNA is chronically elevated in adipose tissue of obese mice and is a powerful inducer of PAI-1 in adipocytes; (2) the adipocyte is the primary insulin-responsive cell in terms of PAI-1; and (3) insulin continues to induce PAI-1 in metabolically insulin-resistant adipocytes and mice. We hypothesize that the increased TGF-beta and hyperinsulinemia in obesity alters the biosynthetic activity of adipocytes and promotes the cardiovascular risk associated with this condition. In Aim 1, we will investigate the regulation and consequences of TGF-beta expression in obesity and during adipogenesis. The possibility that TGF-beta alters preadipocyte growth and differentiation as well as adipocyte gene expression, glucose homeostasis, and insulin-resistance will be explored in vivo and in vitro using specific inhibitors of TGF-beta. In Aim 2, we will examine additional models of murine obesity to determine the generality and tissue specificity of the effects of insulin on PAI-1. We will also employ inhibitors of insulin-signaling to define the pathways that control PAI-1 gene expression, and to test the hypothesis that in adipocytes, glucose homeostasis and PAI-1 gene expression are regulated by different pathways. These studies should provide novel information about TGF-beta and insulin and their respective roles in the regulation of PAI-1 in adipocytes in health and disease.
几乎没有关于促进人类肥胖高凝状态和增加心血管疾病风险的分子机制的信息。尽管纤溶酶原激活物抑制物-1(PAI-1)在肥胖人群中持续显著升高,是动脉粥样硬化性血栓形成的危险因素,但其在肥胖中表达的来源和调控机制(S)仍未明确。我们对肥胖小鼠和培养的脂肪细胞的研究表明,血浆PAI-1的升高是由于脂肪细胞对肿瘤坏死因子-α和胰岛素的反应增加了合成,脂肪细胞可能在人类肥胖的止血基因表达中发挥了以前未被认识到的中心作用。以下观察结果为脂肪细胞和PAI-1在肥胖中的生物合成提供了新的见解,并形成了这一应用的基础:(1)转化生长因子-β(TGF-β)mRNA在肥胖小鼠的脂肪组织中长期升高,并且是脂肪细胞中PAI-1的强大诱导者;(2)脂肪细胞是PAI-1的主要胰岛素反应细胞;(3)胰岛素继续在代谢胰岛素抵抗的脂肪细胞和小鼠中诱导PAI-1。我们假设肥胖症中增加的转化生长因子-β和高胰岛素血症改变了脂肪细胞的生物合成活性,并增加了与这种情况相关的心血管风险。在目标1中,我们将研究转化生长因子-β在肥胖和脂肪形成过程中的表达调节和后果。使用转化生长因子-β的特异性抑制剂,将在体内和体外探索转化生长因子-β改变前脂肪细胞的生长和分化以及脂肪细胞的基因表达、葡萄糖稳态和胰岛素抵抗的可能性。在目标2中,我们将检查其他的小鼠肥胖模型,以确定胰岛素对PAI-1影响的一般性和组织特异性。我们还将使用胰岛素信号抑制剂来确定控制PAI-1基因表达的途径,并检验在脂肪细胞中,葡萄糖稳态和PAI-1基因表达受不同途径调控的假设。这些研究将提供关于转化生长因子-β和胰岛素的新信息,以及它们各自在健康和疾病中调节脂肪细胞中PAI-1的作用。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

DAVID J LOSKUTOFF其他文献

DAVID J LOSKUTOFF的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('DAVID J LOSKUTOFF', 18)}}的其他基金

PLASMINOGEN ACTIVATOR INHIBITOR/VITRONECTIN INTERACTIONS
纤溶酶原激活剂抑制剂/玻连蛋白相互作用
  • 批准号:
    6713653
  • 财政年份:
    2003
  • 资助金额:
    $ 42.81万
  • 项目类别:
Mechanisms of Thrombus Instability
血栓不稳定的机制
  • 批准号:
    6707461
  • 财政年份:
    2003
  • 资助金额:
    $ 42.81万
  • 项目类别:
PLASMINOGEN ACTIVATOR INHIBITOR/VITRONECTIN INTERACTIONS
纤溶酶原激活剂抑制剂/玻连蛋白相互作用
  • 批准号:
    6564878
  • 财政年份:
    2002
  • 资助金额:
    $ 42.81万
  • 项目类别:
PLASMINOGEN ACTIVATOR INHIBITOR/VITRONECTIN INTERACTIONS
纤溶酶原激活剂抑制剂/玻连蛋白相互作用
  • 批准号:
    6414460
  • 财政年份:
    2001
  • 资助金额:
    $ 42.81万
  • 项目类别:
PLASMINOGEN ACTIVATOR INHIBITOR/VITRONECTIN INTERACTIONS
纤溶酶原激活剂抑制剂/玻连蛋白相互作用
  • 批准号:
    6302190
  • 财政年份:
    2000
  • 资助金额:
    $ 42.81万
  • 项目类别:
MECHANISMS OF CARDIOVASCULAR DISEASE IN OBESITY
肥胖引起的心血管疾病的机制
  • 批准号:
    6184071
  • 财政年份:
    1999
  • 资助金额:
    $ 42.81万
  • 项目类别:
MECHANISMS OF CARDIOVASCULAR DISEASE IN OBESITY
肥胖引起的心血管疾病的机制
  • 批准号:
    6012461
  • 财政年份:
    1999
  • 资助金额:
    $ 42.81万
  • 项目类别:
MECHANISMS OF CARDIOVASCULAR DISEASE IN OBESITY
肥胖引起的心血管疾病的机制
  • 批准号:
    6389805
  • 财政年份:
    1999
  • 资助金额:
    $ 42.81万
  • 项目类别:
ENDOTHELIAL CELL MEDIATED FIBRINOLYSIS
内皮细胞介导的纤维蛋白溶解
  • 批准号:
    6307372
  • 财政年份:
    1999
  • 资助金额:
    $ 42.81万
  • 项目类别:
ENDOTHELIAL CELL MEDIATED FIBRINOLYSIS
内皮细胞介导的纤维蛋白溶解
  • 批准号:
    6118080
  • 财政年份:
    1998
  • 资助金额:
    $ 42.81万
  • 项目类别:

相似海外基金

ROLE OF CELL ADHESION IN BIOLOGICAL SIGNAL TRANSDUCTION
细胞粘附在生物信号转导中的作用
  • 批准号:
    6238317
  • 财政年份:
    1997
  • 资助金额:
    $ 42.81万
  • 项目类别:
CELL ADHESION IN BIOLOGICAL SIGNAL TRANSDUCTION
生物信号转导中的细胞粘附
  • 批准号:
    3732412
  • 财政年份:
  • 资助金额:
    $ 42.81万
  • 项目类别:
ROLE OF CELL ADHESION IN BIOLOGICAL SIGNAL TRANSDUCTION
细胞粘附在生物信号转导中的作用
  • 批准号:
    5210031
  • 财政年份:
  • 资助金额:
    $ 42.81万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了