Genomic Variability and Symptomatology After Traumatic Brain Injury

描述（由申请人提供）：创伤性脑损伤（TBI）通常被称为“无声的流行病”，因为它的持久损伤不会留下明显的疤痕，而且公众的认识一直很有限。事实上，创伤性脑损伤标志着一种慢性疾病的开始，目前有530万美国人患有这种疾病，这些症状会导致日常功能的严重限制，并在受伤后的几十年里严重影响生活质量。无论损伤的严重程度如何，76%的创伤性脑损伤幸存者在损伤后一年至少有一种症状，53%至少有三种症状。tbi后最常见的症状是那些影响认知、行为和情感的症状，也是本应用程序关注的重点。这些症状对就业能力、生活质量和家庭动态都有重大影响。目前尚不清楚为什么有些患者完全康复且无症状，而其他具有相同损伤程度、相同护理和相同人口统计学因素的患者却会出现终身症状。我们研究的长期目标是确定影响创伤性脑损伤后症状变异性的生物学基础，并利用这些信息开发针对个体基因组风险概况的循证干预措施。我们的总体目标是确定参与线粒体氧化磷酸化（OXPHOS）途径的基因变异的程度，该途径负责细胞能量的产生，负责脑外伤后认知、行为和情绪相关症状的变异。我们之所以关注OXPHOS通路，是因为细胞能量的可用性会影响脑外伤后神经损伤的程度，我们的初步数据显示线粒体基因组的遗传变异性和OXPHOS通路的效率会影响脑外伤后2年的症状。我们的数据还表明，性别可能会调节线粒体基因型对脑外伤后OXPHOS效率和症状的影响。到目前为止，我们所有的工作都是关于线粒体基因组的；然而，大多数参与OXPHOS通路的基因都是核起源的。该项目将使用标记SNP、候选通路、遗传关联、预测分析方法来评估参与OXPHOS通路的核基因，以研究核和线粒体对脑外伤后认知、行为和情绪症状的影响。该应用程序为我们的研究提供了一个合乎逻辑的下一步，这是必要的，以便充分了解OXPHOS通路的遗传变异性对TBI患者观察到的症状变异性的影响，在包括客观遗传数据的风险预测方面取得进展，并最终将这些发现转化为减少TBI幸存者经历的症状的发生率和严重程度。

DESCRIPTION (provided by applicant): 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.