Role of PAR-1 and PAR-2 in Cardiac Remodeling

PAR-1 和 PAR-2 在心脏重构中的作用

基本信息

  • 批准号:
    7666964
  • 负责人:
  • 金额:
    $ 37.09万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-09-01 至 2011-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Heart disease resulting from pathological cardiac remodeling and hypertrophy is a leading cause of morbidity and mortality in the western world. Protease activated receptors (PARs) are expressed in cardiomyocytes and cardiac fibroblasts. However, their role in cardiac remodeling has not been studied in vivo. Importantly, we demonstrated that PAR-1-/- mice have reduced cardiac remodeling and left ventricle dilation at 2 weeks compared with wild type littermates in a cardiac ischemia-reperfusion (I/R) injury model. Furthermore, we showed that cardiomyocyte-specific overexpression of either PAR-1 or PAR-2 induced cardiac hypertrophy in mice. In addition, we found that PAR-1 and PAR-2 expression was increased in hearts from humans and mice with cardiac hypertrophy. Finally, in vitro studies showed that the activation of PAR-1 or PAR-2 on cardiomyocytes induced hypertrophy. Based on these results, we hypothesize that both PAR-1 and PAR-2 on cardiomyocytes and cardiac fibroblasts contribute to cardiac remodeling after I/R injury. The proposal has two Specific Aims. Specific Aim 1 will determine the role of PAR-1 and PAR-2 in cardiac remodeling after I/R injury. For these experiments, we will use both PAR-1-/- and PAR-2-/- mice, as well as PAR-1 and PAR-2 specific inhibitors. PAR-1flox/flox mice will be generated and crossed with mice expressing the Cre recombinase in either cardiomyocytes or cardiac fibroblasts. These mice will be used to determine the relative contribution of PAR-1 expressed on cardiomyocytes compared with cardiac fibroblasts to cardiac remodeling. Specific Aim 2 will evaluate the role of the MEK5-ERK5, MEK1-ERK1/2 and calcineurin signaling pathways in PAR-1- and PAR-2-dependent hypertrophy of cultured cardiomyocytes by inhibiting these pathways with pharmacologic inhibitors and dominant negative mutants. In addition, we will characterize the different signaling pathways that mediate hypertrophy in the hearts of mice overexpressing either PAR-1 or PAR-2 on cardiomyocytes. These studies will elucidate the role of PAR-1 and PAR-2 in cardiac remodeling after I/R injury and will determine the mechanism by which PAR-1 or PAR-2 activation induces cardiac hypertrophy. The results may lead to the development of PAR-1 and PAR-2 inhibitors that may be used as novel therapies for the treatment of pathological cardiac remodeling and hypertrophy in humans.
描述(由申请人提供):病理性心脏重塑和肥大导致的心脏病是西方世界发病率和死亡率的主要原因。蛋白酶激活受体(PAR)在心肌细胞和心脏成纤维细胞中表达。然而,它们在心脏重塑中的作用尚未在体内研究。重要的是,我们证明了PAR-1-/-小鼠在心脏缺血-再灌注(I/R)损伤模型中,与野生型同窝小鼠相比,2周时心脏重塑和左心室扩张减少。此外,我们发现心肌细胞特异性过表达PAR-1或PAR-2诱导小鼠心肌肥大。此外,我们发现PAR-1和PAR-2的表达增加,从人类和小鼠的心脏肥大。最后,体外研究表明,PAR-1或PAR-2对心肌细胞的激活诱导肥大。基于这些结果,我们假设心肌细胞和心脏成纤维细胞上的PAR-1和PAR-2都有助于I/R损伤后的心脏重构。该提案有两个具体目标。具体目标1将确定PAR-1和PAR-2在I/R损伤后心脏重塑中的作用。对于这些实验,我们将使用PAR-1-/-和PAR-2-/-小鼠,以及PAR-1和PAR-2特异性抑制剂。将产生PAR-1flox/flox小鼠并与在心肌细胞或心脏成纤维细胞中表达Cre重组酶的小鼠杂交。这些小鼠将用于确定与心脏成纤维细胞相比,心肌细胞上表达的PAR-1对心脏重塑的相对贡献。具体目标2将评价MEK 5-ERK 5、MEK 1-ERK 1/2和钙调磷酸酶信号通路在培养心肌细胞PAR-1和PAR-2依赖性肥大中的作用,方法是用药理学抑制剂和显性阴性突变体抑制这些通路。此外,我们将表征不同的信号通路介导的心肌细胞上的PAR-1或PAR-2过表达的小鼠心脏肥大。这些研究将阐明PAR-1和PAR-2在I/R损伤后心脏重塑中的作用,并将确定PAR-1或PAR-2激活诱导心脏肥大的机制。这些结果可能导致PAR-1和PAR-2抑制剂的开发,这些抑制剂可用作治疗人类病理性心脏重塑和肥大的新疗法。

项目成果

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Nigel Mackman其他文献

Nigel Mackman的其他文献

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{{ truncateString('Nigel Mackman', 18)}}的其他基金

Tissue factor-dependent coagulation in thrombosis and immune responses
血栓形成和免疫反应中的组织因子依赖性凝血
  • 批准号:
    10558720
  • 财政年份:
    2021
  • 资助金额:
    $ 37.09万
  • 项目类别:
Role of the Thrombin PAR-1 Pathway in Viral Infection
凝血酶 PAR-1 途径在病毒感染中的作用
  • 批准号:
    9380482
  • 财政年份:
    2013
  • 资助金额:
    $ 37.09万
  • 项目类别:
Role of the Thrombin PAR-1 Pathway in Viral Infection
凝血酶 PAR-1 途径在病毒感染中的作用
  • 批准号:
    8558940
  • 财政年份:
    2013
  • 资助金额:
    $ 37.09万
  • 项目类别:
Role of the Thrombin PAR-1 Pathway in Viral Infection
凝血酶 PAR-1 途径在病毒感染中的作用
  • 批准号:
    8891487
  • 财政年份:
    2013
  • 资助金额:
    $ 37.09万
  • 项目类别:
Role of the Thrombin PAR-1 Pathway in Viral Infection
凝血酶 PAR-1 途径在病毒感染中的作用
  • 批准号:
    8706957
  • 财政年份:
    2013
  • 资助金额:
    $ 37.09万
  • 项目类别:
ROLE OF TISSUE FACTOR IN HEMOSTASIS & THROMBOSIS
组织因子在止血中的作用
  • 批准号:
    8147401
  • 财政年份:
    2010
  • 资助金额:
    $ 37.09万
  • 项目类别:
2010 Hemostasis Gordon Research Conference and/or Gordon Research Seminar
2010 止血戈登研究会议和/或戈登研究研讨会
  • 批准号:
    7911112
  • 财政年份:
    2010
  • 资助金额:
    $ 37.09万
  • 项目类别:
ROLE OF TISSUE FACTOR IN HEMOSTASIS & THROMBOSIS
组织因子在止血中的作用
  • 批准号:
    7667048
  • 财政年份:
    2009
  • 资助金额:
    $ 37.09万
  • 项目类别:
Role of PAR-1 and PAR-2 in Cardiac Remodeling
PAR-1 和 PAR-2 在心脏重构中的作用
  • 批准号:
    7891220
  • 财政年份:
    2007
  • 资助金额:
    $ 37.09万
  • 项目类别:
Role of PAR-1 and PAR-2 in Cardiac Remodeling
PAR-1 和 PAR-2 在心脏重构中的作用
  • 批准号:
    7487314
  • 财政年份:
    2007
  • 资助金额:
    $ 37.09万
  • 项目类别:

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