Epigenetic Influences on Neurobehavioral Recovery following Pediatric Traumatic Brain Injury

项目摘要/摘要 儿童颅脑损伤后预后的不明原因的异质性是最关键的障碍 开发有效的预后工具和治疗方法。我的长期职业目标是发展一种 全面了解发育、遗传、表观遗传、神经病理和环境 影响儿童脑外伤后神经行为恢复的交互作用因素。我将利用这些知识来 将儿童脑外伤领域推向应用个人生物学的精准康复医学 改善个体预测，预测康复反应，并确定新的治疗目标 发展。我是物理医学系的助理教授和KL2学者 在匹兹堡大学医学院接受康复治疗。K01机制对我来说至关重要 获得建立独立研究项目所需的培训和专业知识。 为了填补我在专业知识方面的重大空白，我有五个培训目标：(1)在以下方面获得高级培训 神经表观遗传学，以开发内容专业知识，对甲基化生物样本分析的工作理解， 和表观遗传数据的统计分析和解释方面的技能；(2)获得额外的遗传学培训 分析，侧重于统计遗传学、生物信息资源和精准医学应用；(3)收获 了解脑外伤的细胞和分子神经生物学知识；(4)获得高级统计学方面的额外培训 建模，包括潜在类轨迹分析和结构方程建模；以及(5)开发一个 更广泛地了解公共卫生领域的社会不平等现象。我已经召集了一个多学科的导师 由美国国立卫生研究院资助的研究人员组成的团队，在这些领域都有专业知识。完成我的培训目标 将使我能够分析、解释和传播来自我提议的项目的数据，以及独特的 让我在K01奖励期结束前提交一份竞争性的R01申请。 我提出的研究项目建立在我之前对以下神经行为结果进行表征的工作基础上 儿童脑外伤及其遗传和环境决定因素的研究。拟议的研究将使用 前瞻性、纵向并行队列设计，以检查生物学上的表观遗传影响 相关脑源性神经营养因子通路对200例中重度颅脑损伤患儿神经行为恢复的影响 100名骨科受伤的儿童在急性期(1周)和慢性(6个月和12个月) 恢复。我将描述恢复期BDNF甲基化的特征，并研究这个新的生物标记物 儿童时期的逆境与贫穷之间的已知联系背后潜在的生物学机制 儿童脑外伤后的神经行为结果。在这样做的过程中，我将建立一个数据丰富的生物存储库，它可以 在随后的研究中用于评估许多其他生物标记物和生物学机制 可能有助于儿童脑损伤后的康复，最终将儿童脑损伤领域推向 精准康复医学。

PROJECT SUMMARY/ABSTRACT The unexplained heterogeneity in outcomes following pediatric TBI is the most critical barrier to the development of effective prognostic tools and therapeutics. My long-term career goal is to develop a comprehensive understanding of the developmental, genetic, epigenetic, neuropathological, and environmental factors that interact to influence neurobehavioral recovery from pediatric TBI. I will use this knowledge to advance the field of pediatric TBI towards precision rehabilitation medicine, in which personal biology is used to improve individual prognostication, predict response to rehabilitation, and identify novel targets for treatment development. I am an Assistant Professor and KL2 Scholar in the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh School of Medicine. The K01 mechanism is critical to enable me to acquire the training and expertise necessary to build an independent program of research. To fill crucial gaps in my expertise, I have five training objectives: (1) Obtain advanced training in neuroepigenetics to develop content expertise, a working understanding of methylation biosample analysis, and skills in statistical analysis and interpretation of epigenetic data; (2) Gain additional training in genetic analysis, focusing on statistical genetics, bioinformatic resources, and precision medicine applications; (3) Gain knowledge in cellular and molecular neurobiology of TBI; (4) Obtain additional training in advanced statistical modeling, including latent class trajectory analysis and structural equation modeling; and (5) Develop a broader understanding of social inequalities in public health. I have assembled a multidisciplinary mentorship team of NIH-funded investigators with expertise in each of these areas. Attainment of my training objectives will enable me to analyze, interpret, and disseminate the data from my proposed project, as well as uniquely position me to submit a competitive R01 application prior to the end of the K01 award period. My proposed research project builds upon my prior work characterizing neurobehavioral outcomes following pediatric TBI and examining their genetic and environmental determinants. The proposed study will use a prospective, longitudinal concurrent cohort design to examine the epigenetic influence of the biologically relevant BDNF pathway on neurobehavioral recovery in 200 children with moderate to severe TBI relative to 100 orthopedically injured children during the acute (<1 week) and chronic (6- and 12-mos) phases of recovery. I will characterize BDNF methylation over the recovery period and investigate this novel biomarker as a potential biological mechanism underlying the known association between childhood adversity and poorer neurobehavioral outcomes following pediatric TBI. In so doing, I will establish a data-rich biorepository that can be built upon in subsequent studies for the evaluation of many other biomarkers and biological mechanisms potentially contributing to recovery following pediatric TBI, ultimately moving the field of pediatric TBI toward precision rehabilitation medicine.