Predictive Accuracy of Acute Astroglial Compromise Biomarkers after Traumatic Brain Injury

家长奖摘要 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 创伤性脑损伤是严重的公共卫生负担。在神经创伤研究中，有 长凳和床边之间的巨大脱节，阻碍了新发现更容易地被转化 送进诊所。为此，该项目将为新的基于血液的生物标记物建立伤害基础 将通报脑组织损伤的程度，超过组织丢失的程度，以便及早和客观 评估不同程度的颅脑损伤的伤害负担。星形胶质细胞的健康和易损性 损伤后是持续保护神经元的重要驱动力，因为它们在神经细胞- 血管单位，包括提供代谢物，协调血液流动和维持血脑屏障。 因此，创伤性星形胶质细胞损伤会导致脑能量不足、离子失衡、浮肿、屏障。 泄漏和神经元死亡，因为神经元严重依赖正常的星形胶质功能。 该团队最近发现了一种新的大脑特定的星形胶质损伤定义(AID)生物标记物 由两个细胞损伤释放的标志物和细胞死亡产生的蛋白质片段组成。重要的是，艾滋病 用于评估重型和轻度脑外伤患者的标记物在几个队列中得到了临床验证。反过来说 翻译研究AID标记物早期准确地预测神经创伤后的功能恢复。 在这项建议中，雄性和雌性大鼠皮质挫伤的轻度和中度严重程度将是 用于评估AID生物标记物水平及其与早期星形胶质细胞损伤病理生理的关系 作为总的结果。最重要的假设是：AID的急性损伤后升高和时间分布 生物标志物将与早期星形胶质细胞损伤的程度显著相关，并将准确地预测 行为功能障碍和最终结构结果。这将在本建议书的第一阶段中完成 两个目标集中在：(1)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的相关性 微结构损伤证据，以及(2)确定纵向生物标志物剖面及其预测 慢性伤害负担和行为结果。阶段1的里程碑将：(1)验证AID标记的相关性 急性损伤后脑代谢和损伤严重程度的显微结构证据，以及(2) 证明AID标记物预测微结构和行为缺陷或恢复的准确性 长期如此。成功地通过多种统计标准达到这些里程碑将导致过渡到 第二阶段，将重复轻微伤害实验以评估重复性，并对 闭合性头部损伤评估单次损伤与重复损伤的效果，从而确定是否适用于 模特们。这些生物标志物作为初始损伤程度的准确关联的保真度最终将转化为 并指导对脑外伤患者的诊断监测，实现临床试验的严重程度分层，并提供更好的 康复的预后。

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.