Trauma to developing brain: model refinement and therapeutic intervention

创伤性脑损伤是儿童后天获得性脑损伤最常见的原因，也是儿童死亡和发病的主要原因。改善儿童脑外伤预后的一个关键障碍是缺乏确定创新治疗方法的转化性研究。在这里，我们通过在儿科人群中的平行研究中定义的临床相关措施来验证未成熟脑损伤的小鼠模型，并考虑在实验性脑损伤后，基质金属蛋白酶(MMP)抑制剂在维持长期灰质和白质完整性和保护认知发展方面的有效性。在具体目标1中，通过对26名在2-4岁遭受中到重度脑创伤的青少年的长期跟踪，我们提出了脑成像技术来测量青春期大脑区域体积和白质完整性，重点关注皮质、海马体和胼胝体，这些结构在动物模型和儿童中都显示出急性损伤。在我们的小鼠模型中，使用类似于Morris水迷宫的虚拟迷宫任务来测量记忆，我们将评估遭受早期脑外伤的青少年的导航和空间记忆。为了评估额叶、颞叶和弥漫性病理的影响，我们将评估青少年的执行认知功能和整体功能状况，并分析脑成像结果与认知结果数据的关系。在特定目标2中，出生后21天(PND)的小鼠将接受创伤性脑损伤，然后使用基质金属蛋白酶抑制剂GM6001进行治疗。我们将首先根据神经保护的亚急性解剖学措施来确定该药物的最佳剂量和给药时机。然后，我们将确定这种最佳剂量/时机是否改善了在PND 21受到伤害的中晚期青春期小鼠的长期结果。体视学和功能分析旨在与目标1中的临床措施并行，将用于评估治疗对皮质、海马体和穹隆体积的影响以及海马神经元群体的保存，并使用Morris水迷宫评估认知功能。在这些研究完成后，我们将使用在儿科人群中验证的结果来评估GM6001在脑外伤动物模型中的疗效，这是推进幼儿急性脑损伤治疗并减轻对认知发展的长期影响的必要的第一步。此外，我们引入了测量导航和空间记忆来测试持续早期脑损伤的青少年的海马体功能，这也可能推动这一人群的临床评估技术的进步。

Traumatic brain injury (TBI) is the most frequent cause of acquired brain injury, mortality, and morbidity in young children. A key obstacle to improved outcome of pediatric TBI is the paucity of translational research to identify innovative therapy. Here we address this obstacle by validating a murine model of trauma to the immature brain using clinically relevant measures, as defined in parallel studies in a pediatric population, and consider the efficacy of a matrix metalloproteinase (MMP) inhibitor in maintaining long-term grey and white matter integrity and preserving cognitive development after experimental TBI. In Specific Aim 1, using long term follow-up of 26 adolescents who sustained moderate to severe TBI at age 2-4 years, we propose brain imaging techniques to measure brain region volumes and white matter integrity at adolescence, focusing on the cortex, hippocampus and corpus callosum, structures that show acute damage in both animal models and children. Using a virtual maze task analogous to the Morris Water Maze employed to measure memory in our murine model, we will assess navigation and spatial memory in the adolescents who sustained early TBI. To assess the effects of frontal, temporal, and diffuse pathology, we will evaluate executive cognitive functions and overall functional status in the adolescents and analyze the relation of brain imaging findings to the cognitive outcome data. In Specific Aim 2, mice at postnatal day (pnd) 21 will be subjected to TBI and treated thereafter with the MMP inhibitor GM6001. We will first define an optimal dose and timing of administration of this drug based upon subacute anatomical measures of neuroprotection. We will then determine if this optimal dose/timing improves longer-term outcomes in mid and late adolescent mice who sustained injury at pnd 21. Stereologic and functional assays, designed to parallel the clinical measures in Aim 1, will be used to assess the consequences of treatment on cortex, hippocampus, and corpus callosum volumes and preservation of hippocampal neuronal populations, and to evaluate cognitive function using the Morris Water Maze. At the completion of these studies, we will have evaluated the efficacy of GM6001 in an animal model of TBI using outcomes validated in the pediatric population, a necessary first step toward advancing treatment of acute TBI in young children and mitigating the long term effects on cognitive development. Moreover, our introduction of measuring navigation and spatial memory to test hippocampal function in adolescents who sustained early TBI could also potentially advance clinical assessment techniques in this population.