Role of Acrolein in Spinal Cord Injury

丙烯醛在脊髓损伤中的作用

基本信息

  • 批准号:
    8606665
  • 负责人:
  • 金额:
    $ 33.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-02-15 至 2016-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Physical trauma is only part of the problem in spinal cord injury (SCI): in the days and weeks following damage, oxidative stress plays a critical role in SCI pathology. Despite years of research, conventional strategies aiming to scavenge transient free radicals have not demonstrated any clinical efficacy at curtailing oxidative stress. Evidence indicates that an aldehyde byproduct of lipid peroxidation-acrolein-is elevated following SCI, and that this species is directly toxic to neural tissues, with a much longer half-lfe than the better known reactive oxygen species. Therefore, we hypothesize that acrolein is a key factor in perpetuating oxidative stress following SCI, and thus constitutes a more effective target for therapeutic treatments. We further hypothesize that suppression of acrolein may significantly reduce neuronal damage and enhance functional recovery following SCI. Having demonstrated ample support in vitro and ex vivo, we are now poised to test this hypothesis in vivo through animal models of SCI, an indispensible next step to implicate acrolein as a key factor in SCI. The objective of this application is to ascertain the role of acrolein in post-traumatic pathogenesis in a live animal model of SCI. We will use an established rat spinal cord contusion injury model with three specific aims. First, we seek to quantify the levels of acrolein for multipe severities of injury using high performance liquid chromatography and immunoblotting methods, and correlate those levels with pathological changes in SCI in vivo. Secondly, we will assess the role of acrolein in causing SCI independent of physical trauma by directly injecting varying concentrations of acrolein to the spinal cord of uninjured rats. This experiment will provide crucial evidence to implicate acrolein in secondary injury mechanisms of SCI. Finally, we will evaluate the effectiveness of acrolein binding as therapeutic strategy using two known acrolein scavengers, hydralazine and phenelezine in rat SCI in vivo. The expected outcomes of the proposed work are that we will establish acrolein as an endogenous toxin following spinal cord trauma and a critical factor in secondary expansion of lesions in SCI. By demonstrating that acrolein is a novel, effective target for therapeutic intervention, we expect that existing pharmaceutics can be rapidly translated to clinical therapy for SCI victims, and that new and existing compounds will be investigated for their potential as acrolein scavenging treatments. Such therapeutic strategies could benefit not only spinal cord injury, but also patients with other diseases associated with oxidative stress.
描述(申请人提供):物理创伤只是脊髓损伤(SCI)问题的一部分:在损伤后的几天和几周里,氧化应激在脊髓损伤的病理中起着关键作用。尽管进行了多年的研究,但旨在清除瞬时自由基的传统策略在减少氧化应激方面并未显示出任何临床效果。 有证据表明,在脊髓损伤后,脂质过氧化的副产物--丙烯醛--会升高,而且这种物质对神经组织有直接的毒性,其半衰期比更广为人知的活性氧物种长得多。因此,我们假设丙烯醛是脊髓损伤后持续氧化应激的关键因素,因此构成了一个更有效的靶点。 进行治疗性治疗。我们进一步假设,抑制丙烯醛可以显著减少脊髓损伤后神经元的损伤并促进功能恢复。在证明了体外和体外的充分支持后,我们现在准备通过脊髓损伤的动物模型在体内测试这一假说,这是将丙烯醛作为脊髓损伤关键因素不可或缺的下一步。这项应用的目的是在活体动物模型脊髓损伤中确定丙烯醛在创伤后发病机制中的作用。我们将使用建立的大鼠脊髓挫伤模型,有三个特定的目的。首先,我们试图用高效液相色谱和免疫印迹的方法来量化多种损伤程度的丙烯醛水平,并将这些水平与活体脊髓损伤的病理变化相关联。其次,我们将通过将不同浓度的丙烯醛直接注射到未受损伤的大鼠的脊髓中,评估丙烯醛在引起脊髓损伤中的作用,而不依赖于身体创伤。本实验将为丙烯醛参与脊髓损伤的继发性损伤机制提供重要证据。最后,我们将使用两种已知的丙烯醛清除剂肼和苯丙嗪,在体内评估丙烯醛结合作为治疗策略在大鼠脊髓损伤中的有效性。这项拟议工作的预期结果是,我们将确立丙烯醛是脊髓损伤后的内源性毒素,也是脊髓损伤病变二次扩大的关键因素。通过证明丙烯醛是一种新的、有效的治疗干预靶点,我们预计现有的药物可以迅速转化为SCI患者的临床治疗,新的和现有的化合物将被研究其作为丙烯醛清除治疗的潜力。这样的治疗策略不仅可以使脊髓损伤受益,还可以使其他疾病的患者受益。 与氧化应激有关的疾病。

项目成果

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RIYI SHI其他文献

RIYI SHI的其他文献

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{{ truncateString('RIYI SHI', 18)}}的其他基金

A novel enzymatic mechanism for removing neurotoxic aldehydes after rodent spinal cord injury
啮齿动物脊髓损伤后去除神经毒性醛的新酶机制
  • 批准号:
    10016831
  • 财政年份:
    2019
  • 资助金额:
    $ 33.35万
  • 项目类别:
Biomechanics of Blast Injury
爆炸伤的生物力学
  • 批准号:
    8808857
  • 财政年份:
    2014
  • 资助金额:
    $ 33.35万
  • 项目类别:
Role of Acrolein in Spinal Cord Injury
丙烯醛在脊髓损伤中的作用
  • 批准号:
    8295852
  • 财政年份:
    2012
  • 资助金额:
    $ 33.35万
  • 项目类别:
Role of Acrolein in Spinal Cord Injury
丙烯醛在脊髓损伤中的作用
  • 批准号:
    8890974
  • 财政年份:
    2012
  • 资助金额:
    $ 33.35万
  • 项目类别:
Role of Acrolein in Spinal Cord Injury
丙烯醛在脊髓损伤中的作用
  • 批准号:
    8418695
  • 财政年份:
    2012
  • 资助金额:
    $ 33.35万
  • 项目类别:
NERVE REPAIR BY SYNTHETIC AND BIOLOGICAL POLYMERS
通过合成和生物聚合物修复神经
  • 批准号:
    6546664
  • 财政年份:
    2002
  • 资助金额:
    $ 33.35万
  • 项目类别:
NERVE REPAIR BY SYNTHETIC AND BIOLOGICAL POLYMERS
通过合成和生物聚合物修复神经
  • 批准号:
    6603395
  • 财政年份:
    2002
  • 资助金额:
    $ 33.35万
  • 项目类别:

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