Biomarkers in the Hyperbaric Oxygen in Brain Injury Treatment Trial

脑损伤治疗试验中高压氧的生物标志物

• 批准号: 10741357
• 负责人: Frederick Kofi Korley
• 金额: $ 3.26万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741357
• 关键词: Acute; Astrocytes; Biological Markers; Blood; Brain; Brain Injuries; Cause of Death; Chronic; Clinical Trials; Disease; Dose; Enrollment; Glial Fibrillary Acidic Protein; Head; Hour; Hydrolase; Hyperbaric Oxygen; Individual; Injury; Intracranial Hemorrhages; Intubation; Lesion; Magnetic Resonance Imaging; Measurement; Measures; Monitor; Nerve Degeneration; Nervous System Trauma; Neurons; Orthopedics; Participant; Patients; Plasma; Proteins; Research Project Grants; Role; Sedation procedure; Severities; Subjects Selections; TBI Patients; Therapeutic; Time; Titrations; Traumatic Brain Injury; Ubiquitin; United States; brain abnormalities; clinical examination; comparison control; disability; drug development; individual patient; intervention effect; predictive marker; response; tool; treatment response; treatment trial

Traumatic Brain Injury (TBI) is a major cause of death and disability both in the United States and worldwide. A critical barrier to progress in drug development for TBI is the lack of monitoring biomarkers for assessing individual patient response to treatment. At present, clinical examination remains the fundamental tool for monitoring severe TBI patients and for subject selection in clinical trials. However, these patients are typically intubated and sedated, limiting the utility of clinical examinations. Validated monitoring biomarkers will allow titration of the dose of promising therapeutics to individual subject response, while validated predictive biomarkers make clinical trials more efficient by enabling the enrollment of subjects likely to benefit. A monitoring biomarker is assessed serially over time to measure the status/extent of a disease, or to provide evidence of the effect of an intervention. Blood levels of glial fibrillary acidic protein (GFAP), Ubiquitin Carboxyl Hydrolase L1 (UCH-L1) are promising as monitoring biomarkers for TBI. The scientific premise for their role as monitoring biomarkers is as follows: 1) GFAP and UCH-L1 are both cellular proteins found in astrocytes and neurons respectively. They are predominantly brain-specific. 2) GFAP and UCH- L1 are released post-TBI in amounts that are proportional to injury severity (measured by CT or clinical exam). These biomarkers discriminate between TBI subjects with versus without intracranial hemorrhage on CT. GFAP and UCH-L1 levels can identify TBI patients with structural brain abnormalities that are seen only on MRI and not on head CT. Their levels are correlated with TBI lesion volume as measured by head CT. Put together, this evidence suggests that these biomarkers quantitatively measure the extent of neurodegeneration post- TBI. To date, the variability in GFAP and UCH-L1 levels during the first few hours following injury has not been well characterized. Therefore, it is difficult to distinguish between acute and chronic elevations of GFAP and UCH-L1 based on an initial value. We hypothesize that serial measurements of GFAP and UCH-L1 performed during the first few hours following injury may allow clinicians to distinguish between acute and chronic elevations of GFAP and UCH-L1. The specific aim for the supplementee's research project is: To determine whether there are differences in short-term (2 and 4 hour) changes in plasma GFAP and UCH-L1 levels among patients with acute neurologic injury compared to control subjects who are either 1) healthy or 2) have an acute orthopedic injury but no acute neurologic injury or 3) have a chronic neurologic injury.

创伤性脑损伤（TBI）是美国死亡和残疾的主要原因， 和世界各地。TBI药物开发进展的一个关键障碍是缺乏监测 用于评估个体患者对治疗的反应的生物标志物。目前，临床 检查仍然是监测严重TBI患者和受试者的基本工具， 临床试验中的选择。然而，这些患者通常需要插管和镇静， 临床检查的效用。经验证的监测生物标志物将允许剂量滴定 个体受试者反应的有希望的治疗方法，而经验证的预测生物标志物 通过招募可能受益的受试者，提高临床试验的效率。一 监测生物标志物随时间连续评估以测量疾病的状态/程度， 或提供干预效果的证据。 血液中胶质细胞酸性蛋白（GFAP）、泛素羧基水解酶L1（UCH-L1）水平 有望作为TBI的监测生物标志物。科学前提是他们的作用， 监测生物标志物的方法如下：1）GFAP和UCH-L1都是发现于 星形胶质细胞和神经元。它们主要是大脑特异性的。2)GFAP和UCH- L1在TBI后以与损伤严重程度成比例的量释放（通过CT或MRI测量）。 临床检查）。这些生物标志物区分TBI受试者， CT显示颅内出血GFAP和UCH-L1水平可以识别TBI患者， 脑结构异常，仅在MRI上可见，而在头部CT上看不到。他们的等级 与头部CT测量的TBI病变体积相关。综合起来，这些证据 表明这些生物标志物定量测量了术后神经变性的程度， 创伤性脑损伤到目前为止，在受伤后的最初几个小时内GFAP和UCH-L1水平的变化 还没有得到很好的描述。因此，很难区分急性和 GFAP和UCH-L1在初始值的基础上慢性升高。我们假设连环杀手 在受伤后的最初几个小时内进行GFAP和UCH-L1的测量， 允许临床医生区分GFAP和UCH-L1的急性和慢性升高。 该研究项目的具体目标是： 是血浆GFAP和UCH-L1水平的短期（2和4小时）变化的差异 与对照受试者相比，急性神经损伤患者中， 健康或2）具有急性骨科损伤但没有急性神经损伤或3）具有慢性 神经损伤