Trauma to Immature Brain: Response Repair & Treatment

描述(申请人提供)：创伤性脑损伤是儿童死亡和残疾的主要原因。虽然在动物模型中，许多治疗方法在限制损害方面是有效的，但20多项大型多中心临床试验未能显示出对人类头部损伤的决定性治疗效果。对这种差异的分析表明，模型和试验需要考虑更多的变量，如急性损伤情况、年龄和性别影响。这个问题在儿科头部损伤中变得更加复杂，只有几个动物模型，临床试验甚至更少。大多数关于创伤性脑损伤的研究都是利用啮齿动物，它们在模拟未成熟的人脑方面有很大的局限性。 几年来，我们的实验室一直在使用一种规模化的小猪脑损伤模型，这是一种与人类婴儿和儿童的大脑形态和发育密切相关的物种。这个模型精确地衡量了生物力学损伤对大脑生长的影响，使我们能够研究与人类婴儿、蹒跚学步的儿童和青少年相似的成熟阶段的损伤。我们在急性和慢性损伤反应中都发现了显著的年龄效应，这与设计适合年龄的治疗方法有关。猪在遗传和解剖学上比啮齿类动物更具异质性，在进入治疗试验之前，需要对结果进行急性预测，以进行治疗分层。年龄相关的修复过程和功能结果也必须量化，以便可以测量未成熟期间的治疗效果和毒性。在这项建议中，我们寻求： A)量化包括缺血、癫痫发作和性别在内的急性变量在多大程度上影响每个年龄段受试者的损伤严重程度； B)确定血清损伤标志物(S100B和神经元特异性烯醇化酶)在多大程度上作为发育中仔猪皮质撞击和旋转惯性损伤后损伤严重程度的替代标志物； C)用系列功能磁共振成像和体感诱发电位测量仔猪体感皮质功能恢复的年龄差异。 这项研究的总体目标是利用这些数据开发一个分层治疗试验设计，用于这个规模化的未成熟回脑损伤模型，其中考虑到这些重要的年龄差异对损伤反应的影响。我们相信，这种方法将有助于弥合啮齿动物模型和每年数以千计遭受创伤性脑损伤的儿童的有效治疗之间的差距。

DESCRIPTION (provided by applicant): Traumatic brain injury is the leading cause of death and disability in childhood. While many treatments are effective at limiting damage in animal models, more than 20 large multicenter clinical trials have failed to show conclusive treatment efficacy in human head injury. Analyses of this discrepancy have suggested that models and trials need to take into account more variables such as acute injury conditions, age, and gender effects. The problem is compounded in pediatric head injury, with only a few animal models and even fewer clinical trials. Most research on traumatic brain injury utilizes rodents, which have major limitations in modeling the immature human brain. For several years our laboratory has been utilizing a model of scaled focal brain injury in piglets, a species which closely parallels the brain morphology and development of human infants and children. This model precisely scales the biomechanical injury input for growth of the brain, enabling us to study injury at maturational stages comparable to human infants, "toddlers", and adolescents. We have discovered significant age effects in both acute and chronic injury responses which are relevant to designing age-appropriate treatments. Swine are genetically and anatomically more heterogeneous than rodents, and before moving to treatment trials, acute predictors of outcome are necessary for treatment stratification. Age-dependent repair processes and functional outcomes also must be quantified so that treatment effects and toxicities during immaturity can be measured. In this proposal, we seek to: A) Quantify the degree to which acute variables including ischemia, seizures, and gender contribute to differences in injury severity seen among subjects at each age; B) Determine the extent to which serum injury markers (S100B and neuron-specific enolase) serve as surrogate markers of injury severity after scaled cortical impact and rotational inertial injury in the developing piglet; C) Measure age-dependent differences in functional recovery of the piglet somatosensory cortex using serial functional magnetic resonance imaging and somatosensory evoked potentials. The overall goal of this research is to use these data to develop a stratified treatment trial design for use in this scaled immature gyrencephalic brain injury model which takes these important age differences in injury response into account. We believe this approach will help "bridge the gap" between rodent models and effective treatment for the many thousands of children who suffer traumatic brain injury each year.