Trauma to Immature Brain: Response Repair & Treatment

未成熟大脑的创伤：反应修复

• 批准号: 7215529
• 负责人: Ann-Christine Duhaime
• 金额: $ 34.11万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215529
• 关键词: Accounting; Acute; Adolescent; Age; Animal Model; Animals; Biomechanics; Blood - brain barrier anatomy; Brain; Brain Injuries; Cause of Death; Child; Childhood; Chronic; Clinical Trials; Condition; Craniocerebral Trauma; Data; Development; Diffuse; Disruption; Elevation; Failure; Family suidae; Focal Brain Injuries; Functional Magnetic Resonance Imaging; Gender; Goals; Growth; Histology; Human; Human Development; Impact Seizures; Infant; Injury; Intervention; Ischemia; Laboratories; Lesion; Magnetic Resonance Imaging; Measures; Modeling; Natural regeneration; Neuron-Specific Enolase; Outcome; Pennsylvania; Process; Recovery of Function; Research; Research Personnel; Rodent; Rodent Model; Seizures; Serum; Serum Markers; Severities; Somatosensory Cortex; Somatosensory Evoked Potentials; Source; Staging; Stratification; Study models; Surrogate Markers; Testing; Toddler; Toxic effect; Trauma; Traumatic Brain Injury; Treatment Efficacy; Universities; age difference; age effect; age related; brain morphology; day; density; design; disability; functional outcomes; improved; interest; male; neurogenesis; neuroprotection; programs; repaired; research study; response; response to injury; success; treatment effect; treatment trial

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.

描述（由申请人提供）：创伤性脑损伤是童年死亡和残疾的主要原因。尽管许多治疗方法可有效限制动物模型的损害，但有20多项大型多中心临床试验未能显示出人头损伤的结论性治疗功效。对这种差异的分析表明，模型和试验需要考虑更多变量，例如急性损伤条件，年龄和性别影响。该问题在小儿头部受伤中复杂化，只有几个动物模型，甚至更少的临床试验。大多数关于脑外伤性脑损伤的研究都使用啮齿动物，这些啮齿动物在建模未成熟的人脑时具有重大局限性。 几年来，我们的实验室一直在利用仔猪的鳞片脑损伤模型，该物种与人类和儿童的脑形态和发育紧密相似。该模型准确地扩展了大脑生长的生物力学损伤输入，使我们能够在成熟阶段研究损伤，与人类婴儿，“幼儿”和青少年相当。我们发现与设计适合年龄的治疗有关的急性和慢性损伤反应的年龄影响很大。猪在遗传和解剖学上比啮齿动物更异质，在进行治疗试验之前，对治疗分层的急性预测因素是必要的。还必须量化年龄依赖性修复过程和功能结果，以便可以测量治疗效果和毒性。在此提案中，我们寻求： a）量化包括缺血，癫痫发作和性别在内的急​​性变量的程度有助于每个年龄段受试者之间的损伤严重程度差异； b）确定在发育中的皮层撞击和缩小的皮质冲击和旋转惯性损伤后，还确定血清损伤标记（S100B和神经元特异性烯醇酶）在多大程度上用作损伤严重程度的替代标记； c）使用串行功能性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。 这项研究的总体目的是使用这些数据来开发分层的治疗试验设计，以在此缩放的未成熟脑脑损伤模型中使用，该模型将这些重要的年龄差异考虑到了损伤反应中的这些重要年龄差异。我们认为，这种方法将有助于在啮齿动物模型之间“弥合差距”，并为每年遭受创伤性脑损伤的成千上万儿童的有效治疗。