Genetic and environmental influences on recovery of severe pediatric brain injury.

摘要 儿童创伤性脑损伤(TBI)后的恢复情况有很大的差异。如果我们可以 了解这种变化背后的基础，然后可以优化治疗方法，以减少深刻的 与儿科脑外伤相关的负面社会和经济影响。脑外伤后恢复的预测因素， 尤其是基因和环境的作用，还没有完全被理解。基因和基因的阐明 环境对儿童颅脑损伤后康复的影响是促进儿童脑损伤发展的关键 精准医疗战略。我们小组进行的新的系统生物学分析表明遗传因素 在两个主要的生物过程中，对损伤的反应(细胞增殖、细胞死亡、炎症反应、 细胞代谢)和神经认知和行为储备(神经发育、认知和行为)， 可能与颅脑损伤后的恢复有关。一种寻求识别基因和变异的方法-- 在这些生物过程中表现出来的(基因浓缩)将改善先前的候选基因 接近了。与家庭和家庭环境相互作用的脑损伤后康复相关的基因变异 影响其他儿科人群认知和行为结果的因素；然而， 基因和环境之间的相互作用对儿童脑外伤后康复的影响尚未被探索。这个 这项建议的目的是了解受遗传影响的生物过程和 环境对儿童脑外伤后康复的影响。我们假设基因变异过高 在生物过程中，对创伤性脑损伤恢复的重要作用将与全局、神经认知和 神经行为功能和环境因素会与遗传因素相互作用而影响 小儿重型颅脑损伤后的康复。我们将收集大约338名儿童的唾液DNA样本 参与急性小儿脑外伤试验的方法和决定(ADAPT，U01 NS081041)。这个 主要结果将是由格拉斯哥儿科扩展结果量表评估的全球功能 (Gose)在受伤后3个月、6个月和12个月，次要结果将包括全面评估 在受伤后12个月时的认知和行为功能。我们将使用一种分析方法，寻求 确定与恢复相关的基因和变异，这些基因和变异在以下方面得到了过度表达(基因浓缩) 对损伤的反应以及神经认知和行为储备的生物过程。混合模型分析将是 用来评估基因型与儿童重型颅脑损伤后康复的关系，并阐明 环境因素(家庭功能、育儿实践、家庭环境和 社会经济地位)与经济复苏。遗传和环境因素与遗传和早期临床 影响儿童严重脑外伤后恢复的因素也将被评估。该项目将提供 迫切需要的信息来告知个性化的预后和新的、准确的发展 儿童脑外伤的药物治疗方法，对于这一人群来说是相当缺乏的。

Summary There is substantial variation in recovery after pediatric traumatic brain injury (TBI). If we could understand the underpinnings behind this variation, then treatments could be optimized to reduce the profound negative societal and economic impact associated with pediatric TBI. Predictors of recovery following TBI, particularly the roles of genes and environment, are incompletely understood. Elucidation of genetic and environmental influences on recovery after pediatric TBI is critically needed to advance development of precision medicine strategies. Novel systems biology analyses conducted by our group indicate genetic factors within two main biologic processes, response to injury (cell proliferation, cell death, inflammatory response, cellular metabolism) and neurocognitive and behavioral reserve (neurodevelopment, cognition, and behavior), are likely associated with recovery after TBI. An approach that seeks to identify genes and variants over- represented (gene-enrichment) across these biologic processes would improve upon prior candidate gene approaches. Genetic variants implicated in recovery after TBI interact with home and family environmental factors to influence cognitive and behavioral outcomes in other pediatric populations; however, the effects of the interaction between genes and environment on recovery after pediatric TBI have not been explored. The objective of this proposal is to understand the interplay between genetically influenced biologic processes and environment with respect to recovery after pediatric TBI. We hypothesize that genetic variants overrepresented in biologic processes important to TBI recovery will be associated with global, neurocognitive, and neurobehavioral functioning and that environmental factors will interact with genetic factors to influence recovery after severe pediatric TBI. We will collect salivary DNA samples from approximately 338 children participating in the Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT, U01 NS081041). The primary outcome will be global functioning assessed by the pediatric Glasgow Outcome Scale-Extended (GOSE) at 3, 6, and 12 months post injury and secondary outcomes will include a comprehensive assessment of cognitive and behavioral functioning at 12 months post injury. We will use an analytic approach that seeks to identify genes and variants associated with recovery that are over-represented (gene-enrichment) across response to injury and neurocognitive and behavioral reserve biologic processes. Mixed model analyses will be used to evaluate the association of genotypes with recovery after severe pediatric TBI and to elucidate the association of environmental factors (family functioning, parenting practices, home environment, and socioeconomic status) with recovery. How genetic and environmental factors and genetic and early clinical factors interact to influence recovery after severe pediatric TBI will also be evaluated. This project will provide critically needed information to inform individualization of prognosis and development of novel, precision medicine approaches for pediatric TBI, which are considerably lacking for this population.