IL1 and hypoxic-ischemic insults

IL1 和缺氧缺血性损伤

基本信息

项目摘要

DESCRIPTION (provided by applicant): Injury to the brain caused by cerebral ischemia (i.e. stroke) is a major public health concern. As much as 50% of the brain damage incurred by stroke occurs outside of the primary focus of damage with the process of tissue destruction continuing for hours to days. It is now apparent that inflammatory factors contribute to this delayed pathophysiology. Specifically, studies demonstrate that the cytokine, interleukin 1¿ (IL-1¿), is upregulated following experimental and clinical stroke while additional studies implicate it in the progression of injury. However, the cellular and molecular pathway(s) by which IL-1¿ contributes to neuronal cell death have yet to be identified. This is largely due to the lack of suitable in vitro models in which to assess these mechanisms. Therefore, we developed a reliable and reproducible in vitro model system utilizing mixed neuronal/astrocyte cortical cell cultures. In this model, endogenous production of IL-1¿ is simulated by exogenous addition of IL IL-1¿ and neuronal injury induced by depriving cells of oxygen. We found that pre-treatment? but not concurrent or post-treatment? with this cytokine dramatically potentiated neuronal cell death induced by depriving mixed murine cortical cell cultures of oxygen. The effect of IL-1¿ was concentration-dependent and could be completely inhibited by the recombinant IL-1 receptor antagonist, indicating that signaling through the IL-1 receptor type I (IL1R1) was involved. Further, we found this IL-1¿ -mediated enhancement of hypoxic-neuronal injury can be completely prevented by pharmacological antagonism of metabotropic glutamate receptor 1 (but not mGluRS). This is in stark contrast to a pure hypoxic neuronal injury which is unaffected by mGluRI receptor antagonism. Finally, we found that the enhancement of injury induced by IL-1¿ was dependent on astrocytic expression of IL1R1 whereas loss of signaling in neurons had no effect. Thus, the objectives of this five year research plan are to 1) determine the molecular mechanism(s) by which IL1p signaling functionally synergizes with mGluRI signaling to enhance hypoxic neuronal injury; 2) to determine the astrocytic factor or factors responsible for mediating the IL-1¿ enhancing effect; and 3) to assess whether removal of IL-1¿ signaling can effectively prevent/ameliorate hippocampal injury in vivo induced by direct hippocampal injection of NMDA and/or middle cerebral artery occlusion. Improved definition of these events could lead to the development of new therapeutic strategies designed to attenuate the progression of neuronal destruction following stroke.
描述(由申请人提供):脑缺血(即中风)引起的脑损伤是一个主要的公共卫生问题。多达 50% 的中风造成的脑损伤发生在主要损伤部位之外,组织破坏过程持续数小时至数天。现在很明显,炎症因素导致了这种延迟的病理生理学。具体来说,研究表明细胞因子白细胞介素 1¿ (IL-1¿) 在实验性和临床中风后上调,而其他研究表明它与损伤的进展有关。然而,IL-1 导致神经元细胞死亡的细胞和分子途径尚未确定。这主要是由于缺乏合适的体外模型来评估这些机制。因此,我们利用混合神经元/星形胶质细胞皮层细胞培养物开发了可靠且可重复的体外模型系统。在此模型中,通过外源添加 IL IL-1? 和细胞缺氧诱导的神经元损伤来模拟 IL-1? 的内源性产生。我们发现预处理?但不是同时或治疗后?这种细胞因子显着增强了通过剥夺混合小鼠皮质细胞培养物的氧气而诱导的神经元细胞死亡。 IL-1 的作用具有浓度依赖性,并且可以被重组 IL-1 受体拮抗剂完全抑制,表明涉及通过 I 型 IL-1 受体 (IL1R1) 的信号传导。此外,我们发现这种 IL-1K 介导的缺氧神经元损伤的增强可以通过代谢型谷氨酸受体 1(但不是 mGluRS)的药理学拮抗作用完全阻止。这与不受 mGluRI 受体拮抗作用影响的纯粹缺氧神经元损伤形成鲜明对比。最后,我们发现 IL-1 诱导的损伤增强依赖于 IL1R1 的星形胶质细胞表达,而神经元信号传导的丧失则没有影响。因此,这个五年研究计划的目标是 1) 确定 IL1p 信号传导与 mGluRI 信号传导在功能上协同作用以增强缺氧神经元损伤的分子机制; 2)确定星形胶质细胞因子或负责介导IL-1¿增强作用的因子; 3)评估去除IL-1¿信号是否可以有效预防/改善由直接海马注射NMDA和/或大脑中动脉闭塞引起的体内海马损伤。改进这些事件的定义可能会导致开发新的治疗策略,旨在减轻中风后神经元破坏的进展。

项目成果

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SANDRA J HEWETT其他文献

SANDRA J HEWETT的其他文献

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{{ truncateString('SANDRA J HEWETT', 18)}}的其他基金

Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo
研究系统 xc- 在体内谷氨酸、谷胱甘肽和突触稳态中的作用
  • 批准号:
    10214720
  • 财政年份:
    2020
  • 资助金额:
    $ 10万
  • 项目类别:
Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo
研究系统 xc- 在体内谷氨酸、谷胱甘肽和突触稳态中的作用
  • 批准号:
    10357770
  • 财政年份:
    2018
  • 资助金额:
    $ 10万
  • 项目类别:
Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo
研究系统 xc- 在体内谷氨酸、谷胱甘肽和突触稳态中的作用
  • 批准号:
    10116499
  • 财政年份:
    2018
  • 资助金额:
    $ 10万
  • 项目类别:
Constructing a Conditional Slc7a11 (xCT) Null Mouse
构建条件 Slc7a11 (xCT) 空鼠标
  • 批准号:
    8302237
  • 财政年份:
    2011
  • 资助金额:
    $ 10万
  • 项目类别:
Constructing a Conditional Slc7a11 (xCT) Null Mouse
构建条件 Slc7a11 (xCT) 空鼠标
  • 批准号:
    8203292
  • 财政年份:
    2011
  • 资助金额:
    $ 10万
  • 项目类别:
IL1 and hypoxic-ischemic insults
IL1 和缺氧缺血性损伤
  • 批准号:
    7643047
  • 财政年份:
    2006
  • 资助金额:
    $ 10万
  • 项目类别:
IL-1 in Protection and Injury
IL-1 的保护和损伤作用
  • 批准号:
    8885063
  • 财政年份:
    2006
  • 资助金额:
    $ 10万
  • 项目类别:
IL-1 in Protection and Injury
IL-1 的保护和损伤作用
  • 批准号:
    8731981
  • 财政年份:
    2006
  • 资助金额:
    $ 10万
  • 项目类别:
IL1 and hypoxic-ischemic insults
IL1 和缺氧缺血性损伤
  • 批准号:
    7615077
  • 财政年份:
    2006
  • 资助金额:
    $ 10万
  • 项目类别:
IL-1 in Protection and Injury
IL-1 的保护和损伤作用
  • 批准号:
    9093848
  • 财政年份:
    2006
  • 资助金额:
    $ 10万
  • 项目类别:

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