Traumatic Brain Injury (TBI) is frequently referred to as a """"""""silent epidemic"""""""" because its lasting impairments do not leave visible scars and public awareness has historically been limited. In reality, a TBI marks the beginning of a chronic disease, from which 5.3 million Americans currently suffer persistent symptoms that cause major limitations in daily function and significantly impact quality of life for decades after the injury. Regardless of severity of injury, 76% of TBI survivors have at least one symptom and 53% have at least 3 symptoms at one year post injury. The symptoms seen most frequently post-TBI, and on which this application focuses, are those that influence cognition, behavior, and emotion. These symptoms have a significant impact on employability, quality of life, and family dynamics. It is completely unknown why some patients fully recover and are symptom free, while others who have the same extent of injury, same care, and same demographic factors develop lifelong symptoms. The long-term goal of our research is to identify the biological underpinnings influencing variability in symptomatology post- TBI and to use this information to develop evidence-based interventions that are tailored to an individual's genomic risk profile. Our overall objective of this application is to determine the extent that variability in genes involved in the mitochondrial oxidative phosphorylation (OXPHOS) pathway, responsible for cellular energy production, is responsible for variability in symptoms related to cognition, behavior, and emotion post-TBI. We are focusing on the OXPHOS pathway because availability of cellular energy impacts extent of neurological damage after TBI and our preliminary data shows genetic variability in the mitochondrial genome and efficiency of the OXPHOS pathway impact symptomatology up to 2 years post-TBI. Our data also indicate a possible moderating gender effect on the influence of mitochondrial genotype on both OXPHOS efficiency and symptomatology after TBI. To date all of our work has been with the mitochondrial genome;however the majority of genes involved in the OXPHOS pathway are nuclear in origin. This project will evaluate the nuclear genes involved in the OXPHOS pathway using a tagging SNP, candidate pathway, genetic association, with predictive analysis approach to look at both nuclear and mitochondrial contributions to cognitive, behavioral, and emotional symptomatology post-TBI. This application proposes a logical next step in our line of investigation that is necessary in order to fully understand the impact that genetic variability in the OXPHOS pathway has on symptom variability observed in patients after TBI, progress toward risk prediction that includes objective genetic data, and eventually translate these findings to reduce the incidence and severity of symptoms experienced by survivors of TBI.

Public Health Relevance

Traumatic Brain Injury (TBI) is frequently referred to as a silent epidemic because its lasting impairments do not leave visible scars and public awareness has historically been limited. In reality, a TBI marks the beginning of a chronic disease, from which 5.3 million Americans currently suffer persistent symptoms 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 and are symptom free, while others who have the same extent of injury, same care, and same demographic factors develop lifelong symptoms. The goal of this application is to investigate the role that genetic variability plays in susceptibility to symptoms after TBI with the hope of eventually translating this information into risk assessment and tailored therapies for TBI survivors to reduce the incidence and severity of symptoms post-TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
5R01NR013342-03
Application #
8514736
Study Section
Special Emphasis Panel (ZNR1-REV-M (09))
Program Officer
Tully, Lois
Project Start
2011-09-27
Project End
2014-07-31
Budget Start
2013-08-09
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$357,002
Indirect Cost
$118,203
Name
University of Pittsburgh
Department
Miscellaneous
Type
Schools of Nursing
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jha, Ruchira Menka; Koleck, Theresa A; Puccio, Ava M et al. (2018) Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury. J Neurol Neurosurg Psychiatry 89:1152-1162
Jha, Ruchira M; Elmer, Jonathan; Zusman, Benjamin E et al. (2018) Intracranial Pressure Trajectories: A Novel Approach to Informing Severe Traumatic Brain Injury Phenotypes. Crit Care Med 46:1792-1802
Jha, Ruchira M; Puccio, Ava M; Okonkwo, David O et al. (2017) ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI. Neurocrit Care 26:213-224
Ren, Dianxu; Fan, Jun; Puccio, Ava M et al. (2017) Group-Based Trajectory Analysis of Emotional Symptoms Among Survivors After Severe Traumatic Brain Injury. J Head Trauma Rehabil 32:E29-E37
Osier, Nicole D; Bales, James W; Pugh, Bunny et al. (2017) Variation in PPP3CC Genotype Is Associated with Long-Term Recovery after Severe Brain Injury. J Neurotrauma 34:86-96
Myrga, John M; Failla, Michelle D; Ricker, Joseph H et al. (2016) A Dopamine Pathway Gene Risk Score for Cognitive Recovery Following Traumatic Brain Injury: Methodological Considerations, Preliminary Findings, and Interactions With Sex. J Head Trauma Rehabil 31:E15-29
Failla, Michelle D; Conley, Yvette P; Wagner, Amy K (2016) Brain-Derived Neurotrophic Factor (BDNF) in Traumatic Brain Injury-Related Mortality: Interrelationships Between Genetics and Acute Systemic and Central Nervous System BDNF Profiles. Neurorehabil Neural Repair 30:83-93
Ritter, Anne C; Kammerer, Candace M; Brooks, Maria M et al. (2016) Genetic variation in neuronal glutamate transport genes and associations with posttraumatic seizure. Epilepsia 57:984-93
Failla, Michelle D; Kumar, Raj G; Peitzman, Andrew B et al. (2015) Variation in the BDNF gene interacts with age to predict mortality in a prospective, longitudinal cohort with severe TBI. Neurorehabil Neural Repair 29:234-46
Diamond, Matthew L; Ritter, Anne C; Jackson, Edwin K et al. (2015) Genetic variation in the adenosine regulatory cycle is associated with posttraumatic epilepsy development. Epilepsia 56:1198-206

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