Determinants of vulnerability and recovery after trauma to the developing brain

发育中大脑创伤后脆弱性和恢复的决定因素

基本信息

  • 批准号:
    8870454
  • 负责人:
  • 金额:
    $ 36.2万
  • 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:
    2012-07-01 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) in children is the leading cause of death and disability. Although clinical studies have shown that the developing brain is particularly vulnerable to injury, the basis for this vulnerability remains unclear. TBI to the developing murine brain results in prolonged trafficking of neutrophils into cortical and subcortical structures. We hypothesize that neutrophil elastase (NE) is a determinant of cell injury and a self-propagating inflammatory loop that is driven by an imbalance between NE and its inhibitor, A1- protease inhibitor (A1-PI). With broad substrate specificity and in the absence f adequate local inhibition, excessive NE activity may lead to degradation of the extracellular matrix and exert direct toxic effects on resident cells, events that signal further recruitment of leukocytes into the damaged tissue. We will examine the mechanism underlying proteolytic imbalance, focusing on matrix metalloproteinase-9 (MMP-9). Like NE, MMP-9 is released from activated neutrophils, thus positioning it in proximity to NE. Here we will determine if excessive NE activity arises from inactivation of A1-PI by neutrophil-derived MMP-9. Our general hypothesis is that unopposed NE activity is a key mediator of cell injury after TBI and that strategies to reduce or eliminate its activity will confer neuroprotection and establish an environment that is favorable to brain development and cognitive recovery. Specific Aim 1 will test the hypothesis that unopposed proteolytic activity of NE contributes to a self-propagating inflammatory response. Specific Aim 2 will test the hypothesis that NE, released from activated neutrophils, contributes to cell injury and oxidative stress. Specific Aim 3 will determine if MMP-9 inactivates a1-PI thus allowing NE to produce neural injury and further neutrophil recruitment. Specific Aim 4 will test the hypothesis that pharmacologic blockade of NE will result in long-term structural and behavioral recovery. To address these aims we will use a murine model of TBI at postnatal day 21 and complimentary pharmacologic and genetic strategies to modulate NE activity. We will compare indices of tissue damage in brain injured wildtype (WT) and NE knockout (KO) mice and WT mice treated with a specific inhibitor of NE. To determine the dependency of NE-directed pathogenesis on the over-all activational state of neutrophils, we will study neutrophil-specific SYK-conditional KOs that show a reduced activational state while still retaining NE activity. With state-of-the-art magnetic resonance imaging and a comprehensive battery of behavioral assays, we will further determine if pharmacologic blockage of NE activity supports structural recovery and improves long-term cognitive outcomes. Together, these studies provide an important foundation for understanding the unique vulnerability of the young brain to TBI and for developing the therapies that are specifically tailored to the brain-injured child.
描述(由申请人提供):儿童的创伤性脑损伤(TBI)是死亡和残疾的主要原因。尽管临床研究表明,发育中的大脑特别容易受到伤害,但这种脆弱性的基础尚不清楚。 TBI到发育中的鼠大脑导致嗜中性粒细胞长时间运输到皮质和皮质下结构。我们假设嗜中性粒细胞弹性酶(NE)是细胞损伤的决定因素和由NE及其抑制剂A1-蛋白酶抑制剂(A1-PI)之间的不平衡驱动的自发炎症环的决定因素。由于底物的特异性广泛,并且在不足的局部抑制作用的情况下,过度的NE活性可能导致细胞外基质降解并对居民细胞发挥直接有毒作用,这些事件表明了白细胞进一步募集到受损组织中的事件。我们将检查蛋白水解不平衡的基础机制,重点是基质金属蛋白酶-9(MMP-9)。像NE一样,MMP-9从活化的嗜中性粒细胞中释放出来,因此将其定位在与NE的附近。在这里,我们将确定是否由中性粒细胞衍生的MMP-9灭活A1-Pi是否会产生过多的NE活性。我们的总体假设是,无反应的NE活性是TBI后细胞损伤的关键介体,减少或消除其活性的策略将赋予神经保护并建立一个有利于脑发育和认知恢复的环境。具体目标1将检验以下假设:NE的无反应蛋白水解活性有助于自我传播的炎症反应。特定目标2将检验以下假设:NE从活化的中性粒细胞释放出来有助于细胞损伤和氧化应激。特定的目标3将确定MMP-9是否使A1-PI失活,从而使NE产生神经损伤并进一步嗜中性粒细胞募集。具体目标4将检验以下假设:NE的药理阻滞将导致长期结构和行为恢复。为了解决这些目标,我们将在产后第21天使用TBI的鼠模型,并使用免费的药理学和遗传策略来调节NE活动。我们将比较用特异性NE抑制剂治疗的脑损伤野生型(WT)和NE敲除(KO)小鼠的组织损伤指标。为了确定NE指导发病机理对中性粒细胞过度活化状态的依赖性,我们将研究中性粒细胞特异性SYK条件KOS,这些KOS显示出降低活化状态,同时仍保持NE活性。通过最先进的磁共振成像和全面的行为分析,我们将进一步确定NE活动的药理阻塞是否支持结构恢复并改善长期认知结果。这些研究一起为了解年轻大脑对TBI的独特脆弱性以及开发专门针对脑部受伤儿童而定的疗法提供了重要的基础。

项目成果

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{{ truncateString('LINDA J. NOBLE', 18)}}的其他基金

Determinants of vulnerability and recovery after trauma to the developing brain
发育中大脑创伤后脆弱性和恢复的决定因素
  • 批准号:
    9120429
  • 财政年份:
    2012
  • 资助金额:
    $ 36.2万
  • 项目类别:
Determinants of vulnerability and recovery after trauma to the developing brain
发育中大脑创伤后脆弱性和恢复的决定因素
  • 批准号:
    8484467
  • 财政年份:
    2012
  • 资助金额:
    $ 36.2万
  • 项目类别:
Determinants of vulnerability and recovery after trauma to the developing brain
发育中大脑创伤后脆弱性和恢复的决定因素
  • 批准号:
    8366825
  • 财政年份:
    2012
  • 资助金额:
    $ 36.2万
  • 项目类别:
Determinants of vulnerability and recovery after trauma to the developing brain
发育中大脑创伤后脆弱性和恢复的决定因素
  • 批准号:
    8681563
  • 财政年份:
    2012
  • 资助金额:
    $ 36.2万
  • 项目类别:
Trauma to Developing Brain-Injury and Repair Mechanisms
创伤对脑损伤和修复机制的发展
  • 批准号:
    6965768
  • 财政年份:
    2005
  • 资助金额:
    $ 36.2万
  • 项目类别:
Trauma to Developing Brain-Injury and Repair Mechanisms
创伤对脑损伤和修复机制的发展
  • 批准号:
    7628357
  • 财政年份:
    2005
  • 资助金额:
    $ 36.2万
  • 项目类别:
Trauma to Developing Brain-Injury and Repair Mechanisms
创伤对脑损伤和修复机制的发展
  • 批准号:
    7446689
  • 财政年份:
    2005
  • 资助金额:
    $ 36.2万
  • 项目类别:
Trauma to developing brain-injury and repair mechanisms
创伤导致脑损伤和修复机制的发展
  • 批准号:
    8431806
  • 财政年份:
    2005
  • 资助金额:
    $ 36.2万
  • 项目类别:
Trauma to Developing Brain-Injury and Repair Mechanisms
创伤对脑损伤和修复机制的发展
  • 批准号:
    7099432
  • 财政年份:
    2005
  • 资助金额:
    $ 36.2万
  • 项目类别:
Trauma to developing brain-injury and repair mechanisms
创伤导致脑损伤和修复机制的发展
  • 批准号:
    8064528
  • 财政年份:
    2005
  • 资助金额:
    $ 36.2万
  • 项目类别:

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