Hypertrophy, Heart Failure and PKC

肥厚、心力衰竭和 PKC

基本信息

  • 批准号:
    7214740
  • 负责人:
  • 金额:
    $ 37.63万
  • 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:
    2004-04-01 至 2009-03-31
  • 项目状态:
    已结题

项目摘要

Protein kinase C (PKC) isozymes play a key role in insult-induced cardiac remodeling and the progression to heart failure (HF). Conflicting data on the role of individual PKC isozymes in modulating these functions have been reported, in part due to the use of PKC isozyme non-selective pharmacological tools. Our research identified PKC isozyme-selective inhibitors and activators, which we apply to determine the role of individual isozymes in normal and diseased heart. We identified peptide inhibitors and activators for each isozyme and found that the peptides can be effectively delivered into the heart, in vivo. Using these PKC regulating peptides, we previously showed opposing roles for specific PKC isozymes in various functions; we showed that ePKC activation or delta PKC inhibition provides cardioprotection from ischemia in vitro, ex vivo and recently in vivo. We also found that our isozyme-specific peptide regulators of PKC remain effective when continuously delivered in vivo, for 10 days. Therefore, for the first time, we can determine whether these PKC-regulating peptides can prevent, enhance or reduce cardiac remodeling and transition to heart failure, a study that requires regulation of PKC in a sustained fashion. Due to the limitations of animal models for cardiac remodeling and HF, we plan to use 3 different models, and use the peptides as selective pharmacological tools to determine the role of each PKC isozyme in the development of HF. The first model involves pressure overload using transverse aortic constriction in mice. The second uses pressure overload in hypertensive Dahl rats, which develop reliable cardiac remodeling and heart failure after initiation of a high salt diet. The third model follows post myocardial infarction-induced cardiac remodeling and HF in mice. Peptide regulators of individual isozymes (activators or inhibitors) will be delivered in a sustained fashion at different times during the course of the disease to determine the role of each PKC isozyme in the development of adaptive and maladaptive remodeling and the transition to heart failure. Together, these studies will identify the PKC isozyme(s) that should be targeted for the development of new therapeutics for human heart failure, especially if PKC-based pharmacotherapy is considered
蛋白激酶C(PKC)同工酶在胰岛素诱导的心脏重构和心力衰竭(HF)的进展中起关键作用。个别PKC同工酶在调节这些功能中的作用已被报道,部分原因是PKC同工酶非选择性药理学工具的使用。我们的研究确定了PKC同工酶选择性抑制剂和激活剂,我们应用于确定正常和病变心脏中的单个同工酶的作用。我们确定了每种同工酶的肽抑制剂和激活剂,并发现这些肽可以有效地在体内递送到心脏中。使用这些PKC调节肽,我们以前表现出不同功能的特定PKC同工酶的相反作用,我们表明,ePKC激活或δ PKC抑制提供心肌缺血在体外,离体和最近在体内的保护。我们还发现,我们的PKC同工酶特异性肽调节剂在体内连续递送10天时仍然有效。因此,我们第一次可以确定这些PKC调节肽是否可以预防,增强或减少心脏重塑和向心力衰竭的转变,这项研究需要以持续的方式调节PKC。由于心脏重塑和HF动物模型的局限性,我们计划使用3种不同的模型,并使用肽作为选择性药理学工具来确定每个PKC同工酶在HF发展中的作用。第一个模型涉及使用小鼠中的横向主动脉收缩的压力超负荷。第二种方法是在高血压Dahl大鼠中使用压力超负荷,这种大鼠在开始高盐饮食后发生可靠的心脏重塑和心力衰竭。第三种模型遵循小鼠心肌梗死后诱导的心脏重构和HF。将在疾病过程中的不同时间以持续的方式递送单个同工酶的肽调节剂(激活剂或抑制剂),以确定每种PKC同工酶在适应性和适应不良重塑的发展以及向心力衰竭转变中的作用。总之,这些研究将确定PKC同工酶,其应作为开发人类心力衰竭新疗法的目标,特别是如果考虑基于PKC的药物治疗

项目成果

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DARIA MOCHLY-ROSEN其他文献

DARIA MOCHLY-ROSEN的其他文献

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{{ truncateString('DARIA MOCHLY-ROSEN', 18)}}的其他基金

ALDH Activation to treat Fanconi Anemia
激活 ALDH 治疗范可尼贫血
  • 批准号:
    10178078
  • 财政年份:
    2018
  • 资助金额:
    $ 37.63万
  • 项目类别:
ALDH Activation to treat Fanconi Anemia
激活 ALDH 治疗范可尼贫血
  • 批准号:
    9980975
  • 财政年份:
    2018
  • 资助金额:
    $ 37.63万
  • 项目类别:
Development of a novel treatment for hyperbilirubinemia-induced kernicterus
开发治疗高胆红素血症引起的核黄疸的新疗法
  • 批准号:
    9926721
  • 财政年份:
    2016
  • 资助金额:
    $ 37.63万
  • 项目类别:
Translational Incubator Core
转化孵化器核心
  • 批准号:
    8643875
  • 财政年份:
    2014
  • 资助金额:
    $ 37.63万
  • 项目类别:
Mechanisms of Ethanol-Induced Cardiac Protection
乙醇诱导的心脏保护机制
  • 批准号:
    7860783
  • 财政年份:
    2009
  • 资助金额:
    $ 37.63万
  • 项目类别:
Interfering with Protein-Protein Interaction for the Treatment of Leishmaniasis
干扰蛋白质-蛋白质相互作用治疗利什曼病
  • 批准号:
    7449189
  • 财政年份:
    2008
  • 资助金额:
    $ 37.63万
  • 项目类别:
Interfering with Protein-Protein Interaction for the Treatment of Leishmaniasis
干扰蛋白质-蛋白质相互作用治疗利什曼病
  • 批准号:
    7692203
  • 财政年份:
    2008
  • 资助金额:
    $ 37.63万
  • 项目类别:
Hypertrophy, Heart Failure and PKC
肥厚、心力衰竭和 PKC
  • 批准号:
    7023830
  • 财政年份:
    2004
  • 资助金额:
    $ 37.63万
  • 项目类别:
Hypertrophy, Heart Failure and PKC
肥厚、心力衰竭和 PKC
  • 批准号:
    7386626
  • 财政年份:
    2004
  • 资助金额:
    $ 37.63万
  • 项目类别:
Hypertrophy, Heart Failure and PKC
肥厚、心力衰竭和 PKC
  • 批准号:
    6766324
  • 财政年份:
    2004
  • 资助金额:
    $ 37.63万
  • 项目类别:

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