Epigenetic Influences on Neurobehavioral Recovery following Pediatric Traumatic Brain Injury

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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.