Trauma to Immature Brain: Response Repair & Treatment

描述（由申请人提供）：创伤性脑损伤是儿童死亡和残疾的主要原因。虽然许多治疗方法在动物模型中有效地限制了损伤，但20多项大型多中心临床试验未能显示人类头部损伤的确切治疗效果。对这种差异的分析表明，模型和试验需要考虑更多的变量，如急性损伤条件，年龄和性别影响。这个问题在儿科头部损伤中更为复杂，只有少数动物模型和更少的临床试验。大多数关于创伤性脑损伤的研究利用啮齿动物，这在模拟未成熟的人脑方面具有重大局限性。 几年来，我们的实验室一直在利用一个模型的规模局灶性脑损伤的小猪，一个物种，密切平行的大脑形态和发展的人类婴儿和儿童。该模型精确地缩放了大脑生长的生物力学损伤输入，使我们能够研究与人类婴儿，“幼儿”和青少年相当的成熟阶段的损伤。我们已经发现了急性和慢性损伤反应的显着年龄效应，这与设计适合年龄的治疗方法有关。猪在遗传学和解剖学上比啮齿动物更异质，在进入治疗试验之前，治疗分层需要急性结局预测因子。还必须量化依赖性修复过程和功能结果，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，我们力求： A）量化包括缺血、癫痫发作和性别在内的急性变量对每个年龄的受试者中观察到的损伤严重程度差异的影响程度; B）确定血清损伤标志物（S100 B和神经元特异性烯醇化酶）在发育中的小猪中在成比例的皮质撞击和旋转惯性损伤后作为损伤严重性的替代标志物的程度; C）使用系列功能磁共振成像和体感诱发电位测量小猪体感皮层功能恢复的年龄依赖性差异。 本研究的总体目标是利用这些数据开发一种分层治疗试验设计，用于该比例未成熟脑回损伤模型，该模型考虑了损伤反应的这些重要年龄差异。我们相信这种方法将有助于“弥合啮齿动物模型和有效治疗每年遭受创伤性脑损伤的数千名儿童之间的差距”。

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.