IL1 and hypoxic-ischemic insults

IL1 和缺氧缺血性损伤

基本信息

批准号：
7615077
负责人：
SANDRA J HEWETT
金额：
$ 34.46万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-18 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7615077
关键词：
Address Aftercare Astrocytes Attenuated Biochemical Biological Models Brain Brain Injuries Cell Culture Techniques Cells Cerebral Ischemia Clinical Development Event Evolution Excision Excitatory Amino Acid Receptors Foundations Functional disorder Glutamate Receptor Goals Grant Hippocampus (Brain)Hour Hypoxia IL1R1 gene Infarction Inflammation Inflammation Mediators Inflammatory Injection of therapeutic agent Injury Interleukin-1 Interleukin-1 Receptors Interleukins Ischemia Ischemic Penumbra Lead Ligands Mediating Middle Cerebral Artery Occlusion Modeling Molecular Mus N-Methylaspartate Neuronal Injury Neurons Oxygen Pathway interactions Predisposition Production Public Health Recombinants Research Signal Transduction Simulate Stroke System cell injury cell type cytokine design excitotoxicity improved in vitro Model in vivo metabotropic glutamate receptor type 1 neuron loss neurotrophic factor novel therapeutics prevent receptor receptor expression research study synergism tissue processing

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）：由脑缺血（即中风）引起的脑损伤是一个主要的公共卫生问题，由中风引起的脑损伤中多达 50% 发生在主要损伤部位之外。组织破坏持续数小时至数天，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¿) 在实验和临床中风后上调，而其他研究表明它在损伤的进展中，然而，IL-1¿ 的细胞和分子途径。导致神经细胞死亡的因素尚未确定，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，内源性产生 IL-1¿通过外源添加 IL IL-1 来模拟我们发现，这种细胞因子在治疗前（但不是同时治疗或治疗后）通过剥夺混合小鼠皮质细胞培养物的氧气而显着增强了神经元细胞的死亡。 ¿是依赖性的，并且可以被重组 IL-1 受体拮抗剂完全抑制，表明通过 I 型 IL-1 受体（IL1R1）的信号传导参与其中。此外，我们发现了这种 IL-1¿代谢型谷氨酸受体 1（但不是 mGluRS）的药理拮抗作用可以完全阻止缺氧神经元损伤的增强，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。 IL-1诱导的损伤增强¿依赖于 IL1R1 的星形细胞表达，而神经元信号传导的缺失则没有影响。因此，这个五年研究计划的目标是 1) 确定 IL1p 信号传导与 mGluRI 信号传导功能协同增强缺氧的分子机制。神经元损伤；2) 确定星形胶质细胞因子或负责介导 IL-1¿增强效果；3) 评估是否去除IL-1¿信号传导可以有效预防/改善直接海马注射 NMDA 和/或大脑中动脉闭塞引起的海马损伤。这些事件的定义的改进可能会导致开发旨在减轻中风后神经元破坏进展的新治疗策略。