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

遗传和环境对严重儿童脑损伤恢复的影响。

• 批准号: 9385155
• 负责人: Brad G Kurowski
• 金额: $ 9.97万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-11-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9385155
• 关键词: Acute; Address; Adult; Advanced Development; Age; Behavior; Behavior assessment; Behavioral; Candidate Disease Gene; Caring; Cell Death; Cell Proliferation; Child; Child Rearing; Childhood; Childhood Injury; Clinical; Cognition; Cognitive; DNA; Data Set; Development; Disease; Environment; Environmental Risk Factor; Family; Foundations; Future; Genes; Genetic; Genetic Variation; Genomic approach; Genotype; Glasgow Outcome Scale; Home environment; Individual; Inflammatory Response; Injury; Intervention; Knowledge; Life Style; Link; Longitudinal Studies; Medical; Metabolism; Modeling; Morbidity - disease rate; Neurocognitive; Neurologic; Outcome; Pediatric Brain Injury; Persons; Physiology; Play; Population; Precision therapeutics; Prevention; Process; Recovery; Rehabilitation therapy; Research Infrastructure; Role; Salivary; Sampling; Site; Socioeconomic Status; Systems Biology; Traumatic Brain Injury; Traumatic Brain Injury recovery; Variant; Work; behavioral outcome; cohort; comparative; economic cost; economic impact; genetic approach; genetic variant; improved; individualized medicine; injury and repair; insight; mild traumatic brain injury; mortality; multidisciplinary; neurobehavioral; neurodevelopment; novel; outcome forecast; pediatric traumatic brain injury; personalized approach; precision medicine; primary outcome; response to injury; secondary outcome

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.

总结 小儿创伤性脑损伤（TBI）后的恢复有很大的差异。如果我们能 了解这种变化背后的基础，然后可以优化治疗，以减少深刻的 与儿童TBI相关的负面社会和经济影响。TBI后恢复的预测因素， 特别是基因和环境的作用，还没有完全了解。遗传学和 环境对儿童TBI后恢复的影响是迫切需要的， 精准医疗战略我们小组进行的新的系统生物学分析表明， 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）， 可能与创伤性脑损伤后的恢复有关。一种旨在识别基因和变异的方法- 在这些生物过程中代表的（基因富集）将改善先前的候选基因 接近。TBI与家庭和家庭环境相互作用后恢复的遗传变异 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创伤性脑损伤后恢复的影响尚未研究。的 该提案的目的是了解遗传影响的生物过程之间的相互作用， 儿童TBI后的恢复环境。我们假设遗传变异过度代表 在对TBI恢复重要的生物过程中， 神经行为功能，环境因素将与遗传因素相互作用， 严重小儿TBI后的恢复。我们将收集大约338名儿童的唾液DNA样本 参与急性儿科TBI试验的方法和决策（ADAPT，U 01 NS 081041）。的 主要结局将是通过儿科格拉斯哥结局量表扩展评估的整体功能 （GOSE）在伤后3个月、6个月和12个月时进行评估，次要结局将包括全面评估 在受伤后12个月的认知和行为功能。我们将使用一种分析方法， 识别与恢复相关的基因和变异，这些基因和变异在不同的人群中过度表达（基因富集）， 对损伤的反应以及神经认知和行为储备生物过程。混合模型分析将 用于评估基因型与严重儿童TBI后恢复的相关性，并阐明 环境因素（家庭功能、养育方式、家庭环境和 社会经济地位）恢复。遗传和环境因素以及遗传和早期临床 还将评估影响严重儿童TBI后恢复的相互作用因素。本项目将提供 迫切需要的信息，以告知个性化的预后和开发新的，精确的 儿科TBI的药物治疗方法，这是相当缺乏的这一人群。