Epigenetic Influences on Neurobehavioral Recovery following Pediatric Traumatic Brain Injury

表观遗传对小儿脑外伤后神经行为恢复的影响

• 批准号: 10678647
• 负责人: Amery Treble-Barna
• 金额: $ 12.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10678647
• 关键词: Acute; Age; Animal Model; Area; Behavioral; Biological; Biological Factors; Biological Markers; Biology; Body mass index; Brain-Derived Neurotrophic Factor; Cellular Neurobiology; Child; Childhood; Childhood Injury; Chronic; Data; Development; Emotional; Ensure; Environmental Risk Factor; Epigenetic Process; Equation; Evaluation Studies; Evidence based treatment; Funding; Genes; Genetic; Goals; Heterogeneity; Impaired cognition; Impairment; Individual; Injury; Investigation; Knowledge; Life Style; Mediating; Medical; Medical center; Mentored Research Scientist Development Award; Mentorship; Methodology; Methylation; Modeling; Molecular Neurobiology; Morbidity - disease rate; Neurobiology; Neuronal Plasticity; Orthopedics; Outcome; Pathway interactions; Phase; Physical Medicine; Physical Rehabilitation; Population; Positioning Attribute; Process; Prognosis; Proteins; Psychiatric Diagnosis; Public Health; Recovery; Rehabilitation therapy; Research; Research Personnel; Research Priority; Research Project Grants; Severities; Smoking; Statistical Data Interpretation; Statistical Models; Testing; Therapeutic; Time; Training; Traumatic Brain Injury; Traumatic Brain Injury recovery; United States National Institutes of Health; Universities; Work; biobank; bioinformatics resource; biomarker identification; career; childhood adversity; cohort; design; epigenetic marker; genetic analysis; improved; injured; innovation; medical schools; mortality; multidisciplinary; neurobehavioral; neurogenesis; neuronal survival; neuropathology; novel; novel marker; pediatric traumatic brain injury; precision medicine; predicting response; predictive modeling; prevent; professor; prognostic tool; prognostication; programs; prospective; rehabilitation research; response; sex; skills; social; social disparities; therapy development; treatment response

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.

项目总结/摘要 儿童TBI后结局中无法解释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个 全面了解发育，遗传，表观遗传，神经病理学和环境 影响儿童TBI神经行为恢复的因素。我将利用这些知识 将儿科TBI领域推向精确康复医学，其中使用个人生物学 改善个体的精确度，预测对康复的反应，并确定新的治疗目标 发展我是物理医学系的助理教授和KL 2学者， 匹兹堡大学医学院的康复。K 01的机制是至关重要的， 获得必要的培训和专业知识，以建立一个独立的研究计划。 为了填补我的专业知识的关键空白，我有五个培训目标：（1）获得高级培训， 神经表观遗传学发展内容的专业知识，甲基化生物样品分析的工作理解， 和技能的统计分析和解释的表观遗传数据;（2）获得额外的培训，遗传 分析，侧重于统计遗传学，生物信息学资源和精准医学应用;（3）增益 TBI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。我已经组建了一个多学科导师队伍 由NIH资助的研究人员组成的团队，他们在这些领域都有专业知识。实现我的培训目标 将使我能够分析，解释和传播我所提出的项目的数据，以及独特的 使我能够在K 01奖励期结束前提交具有竞争力的R 01申请。 我提出的研究项目建立在我以前的工作特征神经行为结果以下 儿童TBI和检查他们的遗传和环境决定因素。拟议的研究将使用 前瞻性，纵向同期队列设计，以检查表观遗传的影响，生物学 相关BDNF通路对200例中重度TBI儿童神经行为恢复的影响 100名骨科受伤儿童在急性（<1周）和慢性（6个月和12个月）阶段， 复苏我将描述恢复期BDNF甲基化的特征，并研究这种新的生物标志物， 一种潜在的生物学机制，隐藏在童年逆境和贫困之间已知的联系之下， 儿童TBI后的神经行为结果。这样做，我将建立一个数据丰富的生物储存库， 在随后的研究中建立在许多其他生物标志物和生物学机制的评价上 可能有助于儿童TBI后的恢复，最终将儿童TBI领域推向 精准康复医学