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Applying Systems Biology Methodology To Identify Genetic Factors Possibly Associated with Recovery after Traumatic Brain Injury.

ABSTRACT: Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide. It is linked with a number of medical, neurological, cognitive, and behavioral sequelae. The influence of genetic factors on the biology and related recovery after TBI is poorly understood. Studies that seek to elucidate the impact of genetic influences on neurorecovery after TBI will lead to better individualization of prognosis and inform development of novel treatments, which are considerably lacking. Current genetic studies related to TBI have focused on specific candidate genes. The objectives of this study were to use a system biology-based approach to identify biologic processes over-represented with genetic variants previously implicated in clinical outcomes after TBI and identify unique genes potentially related to recovery after TBI. After performing a systematic review to identify genes in the literature associated with clinical outcomes, we used the genes identified to perform a systems biology-based integrative computational analysis to ascertain the interactions between molecular components and to develop models for regulation and function of genes involved in TBI recovery. The analysis identified over-representation of genetic variants primarily in two biologic processes: response to injury (cell proliferation, cell death, inflammatory response, and cellular metabolism) and neurocognitive and behavioral reserve (brain development, cognition, and behavior). Overall, this study demonstrates the use of a systems biology-based approach to identify unique/novel genes or sets of genes important to the recovery process. Findings from this systems biology-based approach provide additional insight into the potential impact of genetic variants on the underlying complex biological processes important to TBI recovery and may inform the development of empirical genetic-related studies for TBI. Future studies that combine systems biology methodology and genomic, proteomic, and epigenetic approaches are needed in TBI.

SUBMITTER: Kurowski BG

PROVIDER: S-EPMC5510694 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Applying Systems Biology Methodology To Identify Genetic Factors Possibly Associated with Recovery after Traumatic Brain Injury.

Kurowski Brad G BG Treble-Barna Amery A Pitzer Alexis J AJ Wade Shari L SL Martin Lisa J LJ Chima Ranjit S RS Jegga Anil A

Journal of neurotrauma 20170503 14

Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide. It is linked with a number of medical, neurological, cognitive, and behavioral sequelae. The influence of genetic factors on the biology and related recovery after TBI is poorly understood. Studies that seek to elucidate the impact of genetic influences on neurorecovery after TBI will lead to better individualization of prognosis and inform development of novel treatments, which are considerably lacki ...[more]

PMID: 28301983

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Project description:Traumatic brain injury (TBI) represents a critical health problem of which diagnosis, management, and treatment remain challenging. TBI is a contributing factor in approximately one-third of all injury-related deaths in the United States. The Centers for Disease Control and Prevention estimate that 1.7 million people suffer a TBI in the United States annually. Efforts continue to focus on elucidating the complex molecular mechanisms underlying TBI pathophysiology and defining sensitive and specific biomarkers that can aid in improving patient management and care. Recently, the area of neuroproteomics-systems biology is proving to be a prominent tool in biomarker discovery for central nervous system injury and other neurological diseases. In this work, we employed the controlled cortical impact (CCI) model of experimental TBI in rat model to assess the temporal-global proteome changes after acute (1?day) and for the first time, subacute (7?days), post-injury time frame using the established cation-anion exchange chromatography-1D SDS gel electrophoresis LC-MS/MS platform for protein separation combined with discrete systems biology analyses to identify temporal biomarker changes related to this rat TBI model. Rather than focusing on any one individual molecular entity, we used in silico systems biology approach to understand the global dynamics that govern proteins that are differentially altered post-injury. In addition, gene ontology analysis of the proteomic data was conducted in order to categorize the proteins by molecular function, biological process, and cellular localization. Results show alterations in several proteins related to inflammatory responses and oxidative stress in both acute (1?day) and subacute (7?days) periods post-TBI. Moreover, results suggest a differential upregulation of neuroprotective proteins at 7?days post-CCI involved in cellular functions such as neurite growth, regeneration, and axonal guidance. Our study is among the first to assess temporal neuroproteome changes in the CCI model. Data presented here unveil potential neural biomarkers and therapeutic targets that could be used for diagnosis, for treatment and, most importantly, for temporal prognostic assessment following brain injury. Of interest, this work relies on in silico bioinformatics approach to draw its conclusion; further work is conducted for functional studies to validate and confirm the omics data obtained.

Project description:ImportanceOne traumatic brain injury (TBI) increases the risk of subsequent TBIs. Research on longitudinal outcomes of civilian repetitive TBIs is limited.ObjectiveTo investigate associations between sustaining 1 or more TBIs (ie, postindex TBIs) after study enrollment (ie, index TBIs) and multidimensional outcomes at 1 year and 3 to 7 years.Design, setting, and participantsThis cohort study included participants presenting to emergency departments enrolled within 24 hours of TBI in the prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study (enrollment years, February 2014 to July 2020). Participants who completed outcome assessments at 1 year and 3 to 7 years were included. Data were analyzed from September 2022 to August 2023.ExposuresPostindex TBI(s).Main outcomes and measuresDemographic and clinical factors, prior TBI (ie, preindex TBI), and functional (Glasgow Outcome Scale-Extended [GOSE]), postconcussive (Rivermead Post-Concussion Symptoms Questionnaire [RPQ]), psychological distress (Brief Symptom Inventory-18 [BSI-18]), depressive (Patient Health Questionnaire-9 [PHQ-9]), posttraumatic stress disorder (PTSD; PTSD Checklist for DSM-5 [PCL-5]), and health-related quality-of-life (Quality of Life After Brain Injury-Overall Scale [QOLIBRI-OS]) outcomes were assessed. Adjusted mean differences (aMDs) and adjusted relative risks are reported with 95% CIs.ResultsOf 2417 TRACK-TBI participants, 1572 completed the outcomes assessment at 1 year (1049 [66.7%] male; mean [SD] age, 41.6 [17.5] years) and 1084 completed the outcomes assessment at 3 to 7 years (714 [65.9%] male; mean [SD] age, 40.6 [17.0] years). At 1 year, a total of 60 participants (4%) were Asian, 255 (16%) were Black, 1213 (77%) were White, 39 (2%) were another race, and 5 (0.3%) had unknown race. At 3 to 7 years, 39 (4%) were Asian, 149 (14%) were Black, 868 (80%) were White, 26 (2%) had another race, and 2 (0.2%) had unknown race. A total of 50 (3.2%) and 132 (12.2%) reported 1 or more postindex TBIs at 1 year and 3 to 7 years, respectively. Risk factors for postindex TBI were psychiatric history, preindex TBI, and extracranial injury severity. At 1 year, compared with those without postindex TBI, participants with postindex TBI had worse functional recovery (GOSE score of 8: adjusted relative risk, 0.57; 95% CI, 0.34-0.96) and health-related quality of life (QOLIBRI-OS: aMD, -15.9; 95% CI, -22.6 to -9.1), and greater postconcussive symptoms (RPQ: aMD, 8.1; 95% CI, 4.2-11.9), psychological distress symptoms (BSI-18: aMD, 5.3; 95% CI, 2.1-8.6), depression symptoms (PHQ-9: aMD, 3.0; 95% CI, 1.5-4.4), and PTSD symptoms (PCL-5: aMD, 7.8; 95% CI, 3.2-12.4). At 3 to 7 years, these associations remained statistically significant. Multiple (2 or more) postindex TBIs were associated with poorer outcomes across all domains.Conclusions and relevanceIn this cohort study of patients with acute TBI, postindex TBI was associated with worse symptomatology across outcome domains at 1 year and 3 to 7 years postinjury, and there was a dose-dependent response with multiple postindex TBIs. These results underscore the critical need to provide TBI prevention, education, counseling, and follow-up care to at-risk patients.

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Applying Systems Biology Methodology To Identify Genetic Factors Possibly Associated with Recovery after Traumatic Brain Injury.

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Applying Systems Biology Methodology To Identify Genetic Factors Possibly Associated with Recovery after Traumatic Brain Injury.

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