Predictive Accuracy of Acute Astroglial Compromise Biomarkers after Traumatic Brain Injury

诺贝尔奖摘要 缺乏快速、简单和可靠的方法来准确诊断和监测患者的状态 遭受创伤性脑损伤（TBI）是一个重大的公共卫生负担。在神经创伤研究中， 工作台和床边之间的巨大脱节，使新发现无法更容易地被翻译 进了诊所为此，该项目将为新的基于血液的生物标志物建立损伤基础， 将告知脑组织损伤的严重程度，以使早期和客观 评估TBI严重程度范围内的损伤负担。星形胶质细胞的健康和脆弱性 损伤后是持续保护神经元的重要驱动因素，因为它们在神经元损伤中起着关键作用。 血管单位，包括提供代谢物，协调血流和维持血脑屏障。 因此，创伤性星形胶质细胞损伤导致脑能量缺乏、离子失衡、水肿、屏障功能障碍、脑损伤和脑损伤。 泄漏和神经元死亡，因为神经元严重依赖于正常的星形胶质细胞功能。 该团队最近确定了一种新的脑特异性星形胶质细胞损伤定义（AID）生物标志物 由两种细胞损伤释放的标记物和细胞死亡产生的蛋白质片段组成。重要的是，援助 标记物在几个组群中被临床验证用于评估严重和轻度TBI患者。以相反 翻译研究AID标记物早期和准确地预测神经创伤后的功能恢复。 在这项建议中，将在雄性和雌性大鼠中， 用于评估AID生物标志物水平及其与早期星形胶质细胞损伤病理生理学的相关性，以及 作为总体结果。过度假设是：急性损伤后AID的升高和时间分布 生物标志物将与早期星形胶质细胞损伤的程度显著相关，并将准确预测 行为功能障碍和最终的结构结果。这将在本提案的第1阶段完成， 两个目标集中于：（1）将基于血清的生物标志物与急性脑代谢抑制和星形胶质细胞相关， 显微结构损伤证据，和（2）确定纵向生物标志物谱及其预测 慢性损伤负担和行为结果。第1阶段里程碑将：（1）验证AID标记物的相关性 急性损伤后时间损伤严重程度的代谢和显微结构证据，和（2） 证明AID标记物预测微观结构和行为缺陷或恢复的准确性 慢性的通过多项统计标准成功达到这些里程碑将导致过渡到 第二阶段将重复轻度损伤实验，以评估可重复性，并对 闭合性头部损伤，以评估单次与重复损伤的影响，从而确定适用于 模型这些生物标志物作为初始损伤程度的准确相关物的保真度最终将转化为 指导TBI患者的诊断监测，使临床试验的严重程度分层，并提供更好的 预后恢复。

ABSTRACT OF PARENT AWARD The absence of fast, simple, and reliable ways to accurately diagnose and monitor the status of patients suffering from traumatic brain injury (TBI) is a significant public health burden. In neurotrauma research there is a large disconnect between bench and bedside that prevents new discoveries from being more easily translated into the clinic. To that end, this project will establish the injury foundation for new blood-based biomarkers that will inform on the magnitude of brain tissue wounding beyond tissue loss, to enable early and objective assessment of the burden of injury across the spectrum of TBI severities. Astroglial health and vulnerability following injury are important drivers for continued protection of neurons, because of their key roles in the neuro- vascular unit, including providing metabolites, orchestrating blood flow and maintaining the blood-brain barrier. Consequently, traumatic astroglial wounding contributes to brain energy deficits, ion imbalance, edema, barrier leak and neuronal death, because neurons are heavily co-dependent on normal astroglial function. The team recently identified a novel brain specific panel of Astroglial Injury Defined (AID) biomarkers comprised of two cell wounding released markers and cell death generated protein fragments. Importantly, AID markers are clinically validated in several cohorts for assessing severe and mild TBI patients. In reverse translational studies AID markers early and accurately predicted functional recovery after neurotrauma. In this proposal, mild and moderate severity levels of cortical contusion in male and female rat will be used to assess AID biomarker levels and their association with early astroglial injury pathophysiologies, as well as overall outcome. The over-arching hypotheses are that: the acute post-injury rise and temporal profiles of AID biomarkers will significantly correlate with the magnitude of early astroglial injury, and will accurately predict behavioral dysfunction and final structural outcome. This will be accomplished in phase 1 of this proposal over two aims focusing on: (1) correlating serum-based biomarkers to acute brain metabolic depression and astroglial microstructural wounding evidence, and (2) determining longitudinal biomarker profiles and their prediction of chronic injury burden and behavioral outcomes. Phase 1 milestones will: (1) validate AID markers for correlation to cerebro-metabolic and microstructural evidence of injury severity at acute post-injury times, and (2) demonstrate accuracy of AID markers to predict the microstructural and behavioral deficits or recovery chronically. Success in meeting these milestones by passing multiple statistical criteria will result in transition to phase 2 which will repeat the mild injury experiment to assess reproducibility, and conduct new studies on a closed head injury to assess the effect of single versus repeat injury, thus determining applicability across models. Fidelity of these biomarkers as accurate correlates of the initial injury magnitude will ultimately translate and guide diagnostic monitoring of TBI patients, enable severity stratification of clinical trials, and provide better prognosis for recovery.