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“沉默的流行病”，因为其持久的损伤不会留下可见的疤痕，并且公众意识历来有限。事实上，TBI标志着一种慢性疾病的开始，目前有530万美国人患有持续性症状，导致日常功能严重受限，并在受伤后数十年内严重影响生活质量。无论受伤的严重程度如何，76%的TBI幸存者在受伤后一年内至少有一种症状，53%至少有3种症状。TBI后最常见的症状，以及本申请的重点，是那些影响认知，行为和情绪的症状。这些症状对就业能力、生活质量和家庭动态有重大影响。完全不知道为什么有些患者完全康复并且没有症状，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会出现终身症状。我们研究的长期目标是确定影响TBI后神经病学变异性的生物学基础，并利用这些信息制定针对个体基因组风险状况的循证干预措施。本申请的总体目标是确定参与线粒体氧化磷酸化（OXPHOS）途径（负责细胞能量产生）的基因的变异性对TBI后与认知、行为和情绪相关的症状的变异性的程度。我们专注于OXPHOS途径，因为细胞能量的可用性影响TBI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途径的效率影响TBI后2年的神经病学。我们的数据还表明，线粒体基因型对OXPHOS效率和TBI后症状的影响可能存在性别调节效应。迄今为止，我们所有的工作都是在线粒体基因组上进行的;然而，参与OXPHOS途径的大多数基因都是核起源的。该项目将使用标记SNP，候选途径，遗传关联评估参与OXPHOS途径的核基因，并采用预测分析方法来研究核和线粒体对TBI后认知，行为和情感发育的贡献。本申请提出了一个合乎逻辑的下一步，在我们的调查，这是必要的，以充分了解的影响，在OXPHOS途径的遗传变异性对症状变异性观察TBI后的患者，风险预测的进展，包括客观的遗传数据，并最终转化这些发现，以减少TBI幸存者所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.