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多个大型多中心临床试验未能显示出对人类头部损伤的结论性治疗效果。对这种差异的分析表明，模型和试验需要考虑更多的变量，如急性损伤条件、年龄和性别影响。这个问题在儿童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使用的是啮齿动物，这在模拟未成熟的人类大脑方面有很大的局限性。

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.