Traumatic Brain Injury (TBI) is a serious public health issue with 5.3 million Americans currently suffering persistent consequences from their injury that cause major limitations in daily function and significantly impact quality of life for decades after the injury. It is completely unknown why some patients fully recover, while others who have the same extent of injury, same care, and same demographic factors develop lifelong disabilities. The long-term goal of our research is to identify the biological underpinnings influencing variability in patient outcomes post-TBI and to use this information to develop evidence-based interventions that are tailored to an individual's risk profile. Methylation status f DNA is a mechanism by which gene regulation in response to the local environment is regulated. Our overall objective of this pilot study is to characterize serial DNA methylation profiles from DNA representing the daily CNS environment post-TBI. Then to use these data to evaluate if DNA methylation status of genes (nuclear as well as mitochondrial) representing the oxidative phosphorylation (OXPHOS) pathway differentiate patient outcomes post-TBI and then extend the study to explore the potential impact of DNA methylation across the entire nuclear and mitochondrial genome with patient outcomes post-TBI. This project represents a unique opportunity to capitalize on existing DNA samples and extensive longitudinal phenotype data. There is a dearth of projects using genomic/epigenomic tools to understand the biological underpinnings of patient outcomes after TBI and this project represents the first to use a whole nuclear methylome approach as well as a mitochondrial genome methylation approach in serial daily samples of DNA extracted from CSF. This is a novel, high risk project, but the potential for payoff is also high as this approach may provide novel insight into post-TBI sequelae during a window of time after the injury that is amenable to evidence-based intervention. Data generated from this pilot project will be used to inform a larger study designed to determine the impact of DNA methylation on patient outcomes after TBI and to use those data to identify biological underpinnings involved in variability in patient outcomes after TBI with the intention that a bette understanding of these biological underpinnings will lead to development of evidence- based interventions to improve patient outcomes after TBI.