Trauma to developing brain: model refinement and therapeutic intervention

创伤性脑损伤（TBI）是幼儿获得性脑损伤、死亡率和发病率的最常见原因。改善儿童TBI结局的一个关键障碍是缺乏识别创新疗法的转化研究。在这里，我们解决了这个障碍，通过验证小鼠模型的创伤不成熟的大脑使用临床相关的措施，在儿科人群中的平行研究中定义，并考虑疗效的基质金属蛋白酶（MMP）抑制剂在维持长期的灰色和白色物质的完整性，并保留认知发展后，实验性脑外伤。在具体目标1中，使用26名在2-4岁时持续中度至重度TBI的青少年的长期随访，我们提出了脑成像技术来测量青春期的脑区域体积和白色物质完整性，重点是皮质、海马和胼胝体，这些结构在动物模型和儿童中都显示出急性损伤。使用类似于Morris水迷宫的虚拟迷宫任务来测量小鼠模型的记忆，我们将评估早期TBI青少年的导航和空间记忆。为了评估额叶、颞叶和弥漫性病变的影响，我们将评估青少年的执行认知功能和整体功能状态，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，将出生后第21天（pnd）的小鼠进行TBI，然后用MMP抑制剂GM 6001处理。我们将首先根据神经保护的亚急性解剖学措施来确定这种药物的最佳剂量和给药时间。然后，我们将确定这种最佳剂量/时间是否改善了在pnd 21时遭受损伤的中晚期青春期小鼠的长期结果。体视学和功能测定（旨在与目标1中的临床测量平行）将用于评估给药对皮质、海马和胼胝体体积以及海马神经元群保存的影响，并使用Morris水迷宫评价认知功能。在这些研究完成时，我们将使用在儿科人群中验证的结果评估GM 6001在TBI动物模型中的疗效，这是推进幼儿急性TBI治疗和减轻对认知发育的长期影响的必要的第一步。此外，我们引入测量导航和空间记忆来测试早期TBI青少年的海马功能，也可能推进该人群的临床评估技术。

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.