Systemic activation of caspase-1 dependent interleukins and matrix-metalloproteinases in developmental brain trauma

发育性脑损伤中 caspase-1 依赖性白细胞介素和基质金属蛋白酶的系统激活

• 批准号: 68237052
• 负责人: Professorin Dr. Angela Rösen-Wolff, since 6/2009
• 金额: --
• 依托单位: University of Wisconsin-Madison
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/68237052?language=en
• 关键词: Systemic; activation; caspase; dependent; interleukins

Traumatic brain injury (TBI) is a major cause of morbidity in the pediatric population. We have developed an animal model to study TBI in the developing rat brain and described that trauma triggers rapid excitotoxic and delayed apoptotic neuronal death. During the ongoing period of support of this project we explored the role of caspase-1 dependent interleukins and matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) in infant TBI and found that they are activated following trauma and represent potentially promising therapeutic targets. Blockade of IL-18 action by IL-18 binding protein conferred neuroprotection in infant rats subjected to traumatic brain injury. Also, blockade of MMP action with a metalloproteinase inhibitor confers neuroprotection. In addition, systemic activation of caspase-1 dependent interleukins and MMPs occurs in peripheral organs depending on the severity of the traumatic brain injury. In the continuation period of this project we want to identify the cell types and explore the neurohumoral mechanisms which mediate systemic activation of caspase-1 dependent interleukins and MMPs following infant TBI with focus on the vegetative nervous system. Furthermore we want to determine whether pharmacological inhibition of the systemic inflammatory response following TBI may influence the extent of brain injury.

创伤性脑损伤（TBI）是儿科人群发病的主要原因。我们已经开发了一种动物模型来研究发育中的大鼠脑中的TBI，并描述了创伤触发快速兴奋性毒性和延迟性凋亡神经元死亡。在该项目的持续支持期间，我们探索了caspase-1依赖性白细胞介素和基质金属蛋白酶2和9（MMP-2和MMP-9）在婴儿TBI中的作用，发现它们在创伤后被激活，代表了潜在的有希望的治疗靶点。通过IL-18结合蛋白阻断IL-18的作用对创伤性脑损伤的幼鼠具有神经保护作用。此外，用金属蛋白酶抑制剂阻断MMP作用赋予神经保护作用。此外，依赖于半胱天冬酶-1的白细胞介素和MMP的系统性活化发生在外周器官中，这取决于创伤性脑损伤的严重程度。在这个项目的延续期，我们希望确定细胞类型，并探讨神经体液机制，介导系统激活的caspase-1依赖性白细胞介素和基质金属蛋白酶的婴儿TBI后，重点是植物神经系统。此外，我们还想确定TBI后全身炎症反应的药理学抑制是否会影响脑损伤的程度。