Mitochondrial Genetics of Recovery After Brain Injury

描述（由申请人提供）：该国创伤性脑损伤（TBI）相关死亡和残疾的程度支持调查与TBI后获得的功能结局相关的因素。TBI受害者获得的功能结果水平是高度可变的，即使年龄，损伤和护理相似，但是这种可变性的基础从未得到充分解释，并且可能是TBI后改善患者结果的关键。本研究将采取个体遗传变异可能在TBI后获得的功能结果水平中发挥作用的方法，并将特别关注个体线粒体遗传学和线粒体能量产生。匹兹堡大学的脑创伤研究中心（BTRC）提供了一项关于TBI后恢复遗传学研究的TBI患者的良好特征队列。生物标本和数据库，是可行的每个主题将使我们能够回答我们的假设，在一个有效的和具有成本效益的方式。静脉血采样将使我们能够调查个体的线粒体DNA（mtDNA）是否存在于体质上影响TBI后获得的功能结果。在损伤后的前五天内每12小时收集一次脑脊液（CSF）样本，这将使我们能够研究脑损伤环境中存在的mtDNA是否影响TBI后获得的功能结果，包括异质性的研究。CSF样本还将允许我们在损伤后的前五天内测量脑损伤环境中的线粒体能量产生，以确定线粒体能量产生是否影响TBI后获得的功能结果。文献以及我们的初步数据支持这一调查路线。我们在这些TBI患者的一个子集中检测到mtDNA的缺失，并将缺失与这些受试者的功能结果降低和线粒体能量产生降低相关联。这项研究将帮助我们更好地了解线粒体在人类TBI后获得的功能结果中的作用，并通过帮助临床医生识别需要更积极治疗的患者，提供更适当和更早的干预，并开发有针对性的个性化治疗，以改善TBI后的患者结局，从而产生显着的临床影响。

DESCRIPTION (provided by applicant): The magnitude of traumatic brain injury (TBI) related death and disability in this country supports investigating factors related to functional outcome attained after a TBI. The level of functional outcome that is attained by a TBI victim is highly variable, even when age, injury and care are similar, however the basis for this variability has never been adequately explained, and may hold the key to improving patient outcomes after a TBI. This study will take the approach that individual genetic variation may play a role in level of functional outcome attained after TBI and will specifically focus on individual mitochondrial genetics and mitochondrial energy production. A well-characterized cohort of TBI patients who have agreed to participate in a study on the genetics of recovery after TBI is available through the Brain Trauma Research Center (BTRC) at the University of Pittsburgh. The biological specimens and database that are viable for each subject will allow us to answer our hypotheses in an efficient and cost-effective manner. Venous blood sampling will allow us to investigate whether an individual's mitochondrial DNA (mtDNA) that is present constitutionally influences functional outcome attained after TBI. Cerebrospinal fluid (CSF) samples collected every 12 hours over the first five days after injury will allow us to investigate whether the mtDNA that is present in the environment of the brain injury influences functional outcome attained after TBI, including investigation of heteroplasmy. The CSF samples will also allow us to measure mitochondrial energy production in the environment of the brain injury over the first five days after injury to determine whether mitochondrial energy production influences functional outcome attained after TBI. The literature as well as our preliminary data supports this line of investigation. We have detected deletions in the mtDNA in a subset of these TBI patients and have correlated the deletion to reduced functional outcome and reduced mitochondrial energy production in these subjects. This line of investigation will help us better understand the role of mitochondria in functional outcome attained after TBI in humans and could have a significant clinical impact by helping clinicians to identify patients that require more aggressive therapies, provide more appropriate and earlier intervention, and develop targeted individualized therapy with the intention of improving patient outcomes after TBI.