Mitochondrial Genetics of Recovery After Brain Injury

描述(由申请人提供)：在这个国家，与创伤性脑损伤(TBI)相关的死亡和残疾的程度支持调查与脑损伤后获得的功能结果相关的因素。即使在年龄、损伤和护理相似的情况下，脑外伤患者所达到的功能结果水平也是高度可变的，然而这种差异的基础从未得到充分的解释，可能是改善脑外伤后患者结果的关键。本研究将采取个体遗传变异可能影响脑外伤后功能恢复水平的方法，并将重点放在个体线粒体遗传学和线粒体能量产生上。匹兹堡大学脑创伤研究中心(BTRC)提供了一组同意参与一项关于脑损伤后恢复遗传学研究的脑损伤患者的特征良好的队列。对于每个受试者都可行的生物标本和数据库将使我们能够以有效和经济的方式回答我们的假设。静脉采血将使我们能够调查个体存在的线粒体DNA(MtDNA)是否在体质上影响脑外伤后的功能结果。在脑损伤后的头五天，每12小时采集一次的脑脊液(CSF)样本将使我们能够调查脑损伤环境中存在的mtDNA是否会影响脑损伤后的功能结果，包括异质性的调查。脑脊液样本还将使我们能够测量脑损伤后前五天内脑损伤环境中线粒体的能量产生，以确定线粒体能量产生是否影响脑损伤后的功能结果。文献和我们的初步数据支持这一调查路线。我们在这些脑损伤患者中发现了线粒体DNA的缺失，并将这种缺失与这些受试者的功能结局和线粒体能量产生减少联系起来。这一系列研究将帮助我们更好地了解线粒体在人类脑损伤后功能转归中的作用，并可能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措施以及开发有针对性的个性化治疗来改善脑损伤后的患者结果，从而产生重大的临床影响。

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.