Novel Insights into Ischemic-Induced Cardiac Remodeling

对缺血引起的心脏重塑的新见解

基本信息

  • 批准号:
    9934694
  • 负责人:
  • 金额:
    $ 1.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-01-15 至 2021-10-31
  • 项目状态:
    已结题

项目摘要

Project Summary DJ-1 is a cytoprotective protein that is activated by oxidative stress. Due in large part to the association of DJ-1 with Parkinson's Disease, most studies aimed at investigating its role in response to pathological stimuli have been confined to the brain or neuronal cells. However, DJ-1 is expressed in the heart where it also possesses cytoprotective actions. Studies indicate that DJ-1 plays an important role in multiple cellular processes, including oxidative stress response, anti-apoptotic signaling, and transcriptional regulation. However, the cellular mechanisms underlying these reported actions remain largely unknown. Given that DJ-1 is a small, dimeric, single-domain protein, it either possesses multiple functions to account for these actions or there is a single biochemical activity that explains all of them. What is known is that DJ-1 is activated by the removal of a 15-amino acid peptide at its C terminus in response to oxidative stress. We recently provided the first evidence that DJ-1 is activated within hours following the onset of acute myocardial ischemia-reperfusion (I/R). Preliminary studies from our lab demonstrate that cardiac DJ-1 remains active for up to 7 days following the onset of ischemic injury. Furthermore, our studies revealed that DJ-1 deficient mice displayed worse cardiac dysfunction in response to ischemic-induced heart failure compared to wild-type mice. Elevated levels of hypertrophy, fibrosis, and inflammation accompanied the worse cardiac dysfunction in the DJ-1 deficient mice. More importantly, we provide novel evidence that the delivery of the active form of DJ-1 using recombinant adeno-associated virus 9 (AAV9-DJ1WTΔC) reduces the development of ischemic-induced heart failure. This is the first and only demonstration that an active form of DJ-1 provides cytoprotection in an in vivo model of injury. In this proposal, we will expand on our previous findings and attempt to fill knowledge gaps in the literature regarding the cellular actions of DJ-1. 3 specific aims have been proposed. Aim 1 will determine if DJ- 1 is a novel cardiac deglycase that opposes glycative stress. Aim 2 will determine if DJ-1 attenuates ischemic- induced heart failure by promoting the cardioprotective actions of thioredoxin. Aim 3 will determine if DJ-1 opposes TGF-β signaling by regulating the cardiac expression of Arkadia.
项目摘要 DJ-1是一种由氧化应激激活的细胞保护蛋白。很大程度上是因为DJ-1 对于帕金森氏病,大多数旨在研究其对病理刺激的反应的研究都 被限制在大脑或神经细胞中。然而,DJ-1在心脏中表达, 细胞保护作用。研究表明DJ-1在多种细胞过程中起重要作用, 包括氧化应激反应、抗凋亡信号传导和转录调节。但 这些已报道的作用的细胞机制在很大程度上仍然未知。鉴于DJ-1是一个小, 二聚体,单结构域蛋白,它要么拥有多种功能,以解释这些行动,或者有一个 单一的生物化学活动可以解释所有的症状已知的是,DJ-1是通过移除 15-在其C末端的氨基酸肽响应氧化应激。我们最近提供了第一个证据 DJ-1在急性心肌缺血-再灌注(I/R)发作后数小时内被激活。 我们实验室的初步研究表明,心脏DJ-1在心肌缺血后长达7天仍保持活性。 缺血性损伤的发生。此外,我们的研究表明,DJ-1缺陷小鼠表现出更差的心脏, 与野生型小鼠相比,在响应缺血诱导的心力衰竭的功能障碍中,水平升高 肥大、纤维化和炎症伴随着DJ-1缺陷小鼠中更严重的心功能障碍。 更重要的是,我们提供了新的证据表明,使用重组蛋白递送DJ-1的活性形式, 腺相关病毒9(AAV 9-DJ 1 WT ΔC)可减少缺血性心力衰竭的发生。这 是第一个也是唯一的证明,DJ-1的活性形式在体内模型中提供细胞保护, 损伤在本提案中,我们将扩大我们以前的发现,并试图填补知识空白, 关于DJ-1的细胞作用的文献。提出了三个具体目标。目标1将决定DJ- 1是一种新的抗应激的心脏去糖酶。目标2将确定DJ-1是否减轻缺血性- 通过促进硫氧还蛋白的心脏保护作用诱导心力衰竭。目标3将决定DJ-1 通过调节Arkadia的心脏表达来对抗TGF-β信号传导。

项目成果

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John Winter Calvert其他文献

John Winter Calvert的其他文献

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{{ truncateString('John Winter Calvert', 18)}}的其他基金

Regulation of CSE-Derived Hydrogen Sulfide in the Heart
CSE 衍生的硫化氢在心脏中的调节
  • 批准号:
    10659832
  • 财政年份:
    2023
  • 资助金额:
    $ 1.82万
  • 项目类别:
Novel Insights into Ischemic-Induced Cardiac Remodeling
对缺血引起的心脏重塑的新见解
  • 批准号:
    10063890
  • 财政年份:
    2018
  • 资助金额:
    $ 1.82万
  • 项目类别:
Targeting the orphan nuclear receptor LRH-1 with small molecules
用小分子靶向孤儿核受体 LRH-1
  • 批准号:
    9403854
  • 财政年份:
    2017
  • 资助金额:
    $ 1.82万
  • 项目类别:
Targeting the orphan nuclear receptor LRH-1 with small molecules
用小分子靶向孤儿核受体 LRH-1
  • 批准号:
    10660545
  • 财政年份:
    2017
  • 资助金额:
    $ 1.82万
  • 项目类别:
Targeting the orphan nuclear receptor LRH-1 with small molecules
用小分子靶向孤儿核受体 LRH-1
  • 批准号:
    10681892
  • 财政年份:
    2017
  • 资助金额:
    $ 1.82万
  • 项目类别:
Hydrogen sulfide attenuates heart failure through Nrf2-mediated signaling
硫化氢通过 Nrf2 介导的信号传导减轻心力衰竭
  • 批准号:
    8383492
  • 财政年份:
    2010
  • 资助金额:
    $ 1.82万
  • 项目类别:
Hydrogen sulfide attenuates heart failure through Nrf2-mediated signaling
硫化氢通过 Nrf2 介导的信号传导减轻心力衰竭
  • 批准号:
    7767448
  • 财政年份:
    2010
  • 资助金额:
    $ 1.82万
  • 项目类别:
Hydrogen sulfide attenuates heart failure through Nrf2-mediated signaling
硫化氢通过 Nrf2 介导的信号传导减轻心力衰竭
  • 批准号:
    8011451
  • 财政年份:
    2010
  • 资助金额:
    $ 1.82万
  • 项目类别:
Hydrogen sulfide attenuates heart failure through Nrf2-mediated signaling
硫化氢通过 Nrf2 介导的信号传导减轻心力衰竭
  • 批准号:
    8197419
  • 财政年份:
    2010
  • 资助金额:
    $ 1.82万
  • 项目类别:
Hydrogen sulfide attenuates heart failure through Nrf2-mediated signaling
硫化氢通过 Nrf2 介导的信号传导减轻心力衰竭
  • 批准号:
    8586340
  • 财政年份:
    2010
  • 资助金额:
    $ 1.82万
  • 项目类别:

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