Regulation and Implication of Hemoglobin Clearance in Subarachnoid Hemorrhagic Patients

蛛网膜下腔出血患者血红蛋白清除率的调节及意义

• 批准号: 9332485
• 负责人: Sylvain DORE
• 金额: $ 19.39万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332485
• 关键词: Acute; Admission activity; Adult; Age of Onset; American; Aneurysmal Subarachnoid Hemorrhages; Arteries; Bilirubin; Binding Proteins; Biochemical; Biological Markers; Blood; Brain; Brain hemorrhage; Cerebral Ischemia; Cerebrovascular Spasm; Cessation of life; Clinical; Clinical Data; Collection; Complex; Critical Care; Critical Illness; Data; Development; Disease; Event; Evolution; Extravasation; Ferritin; Functional disorder; Future; Genetic; Genotype; Glasgow Outcome Scale; Haptoglobins; Health Care Costs; Hemoglobin; Hemoglobin concentration result; Hemolysis; Hemopexin; Hemorrhage; Hospitals; Incidence; Individual; Infarction; Inflammatory; Intensive Care Units; Iron; Ischemia; Ischemic Stroke; Measures; Methods; Monitor; Morbidity - disease rate; Nervous System Trauma; Neurologic; Outcome; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Play; Process; Production; Prognostic Marker; Proteome; Public Health; Publishing; Recurrence; Regulation; Reporting; Resolution; Risk; Risk Factors; Serum; Severities; Solid; Standardization; Stroke; Subarachnoid Hemorrhage; Subarachnoid Space; Testing; Therapeutic; Time; Transferrin; Vasodilator Agents; Work; analytical method; base; biomarker development; diagnostic biomarker; disability; functional disability; functional outcomes; hemodynamics; improved outcome; insight; mortality; novel; oxidation; pre-clinical; predictive tools; prospective; standard of care; stroke therapy; therapeutic target; tool; vasoconstriction

Acute aneurysmal subarachnoid hemorrhage (aSAH) is a complex and multifaceted disorder that plays out over days to weeks. Because of this relationship between cerebrovasospasm (CV), delayed cerebral ischemia (DCI), and poor SAH outcomes, there have been unsuccessful efforts made to establish treatments that decrease the incidence of CV. Identifying a predisposing genetic factor and/or biomarker for the early prediction of CV would serve as a clinically useful tool in the critical care management of aSAH patients. Knowing that CV peaks at 7-9 days post SAH, we have a unique therapeutic window here–as long as we have the right predictive tools. Following aSAH, hemolysis in the subarachnoid space releases large amounts of free hemoglobin (Hb). This toxic pro-oxidative and pro-inflammatory Hb and metabolites (iron, bilirubin, and bilirubin oxidation products) are then directly in extravascular contact with the main arteries supplying the brain. A few studies have suggested that changes in the Hb concentrations within the subarachnoid space (i.e. CSF) tend to mirror the evolution of CV; although, the mechanisms by which free Hb may cause this delayed CV are poorly understood. Haptoglobin, hemopexin, sCD163, transferrin, and ferritin are some of the main detoxifying binding proteins against toxic free Hb and metabolites. Indeed, we have recently reported in PNAS that haptoglobin 2-2 genotype could be an independent risk factor for CV, DCI, and poor long-term functional SAH outcomes, likely as a result of ineffective management and clearance of free Hb from the subarachnoid space. Here, we plan to test this hypothesis by detailed mechanistic analyses and simultaneously extend these results to prognostic and diagnostic biomarker development using two complementary analytical methods: 1) unbiased broad profiling with an iTRAQ nanoflow LC-MS/MS-based approach, and 2) targeted profiling on a luminex-based Multi-Analyte Profile platform. Inclusion of such proteome profiling approach provides a strong exploratory aspect to this R21 proposal that is most likley to provide additional unbiased novel pathways. Aim 1: To investigate the biomarker potential of toxic hemoglobin and metabolites in predicting key aSAH clinical events. Aim 2: To investigate the biomarker potential of the protective hemoglobin and metabolite- binding proteins in predicting key aSAH clinical events. Paired serum and CSF levels of Hb, metabolites, and protective binding proteins will be measured at admission and at 6h intervals thereafter for up to 14d post- bleed. These temporal profiles will be correlated to the incidence, severity, and dynamics of CV (rise, peak, resolution), incidence of DCI, mortality, and functional outcomes at discharge, 6wk, and 12mo post-bleed. We have already collected the majority of this clinical data in a standardized manner. Together, this approach will allow the potential development of candidate prognostic and diagnostic biomarkers and may provide a better/novel mechanistic understanding of the dynamics of blood clearance after aSAH. As such, we expect to be able to identify the most opportune key players in these pathways for future therapeutic targeting.

急性动脉瘤亚蛛网膜下腔出血（ASAH）是一种复杂而多方面的疾病 在几天到几周的时间里。由于脑疗法（CV）之间的这种关系，脑缺血延迟 （DCI）和糟糕的SAH结果，已经做出了不成功的努力，以建立治疗方法 减少简历的事件。鉴定早期的易感遗传因素和/或生物标志物 简历的预测将在asah患者的重症监护管理中成为临床上有用的工具。 知道CV在SAH后7-9天达到峰值，只要我们有一个独特的治疗窗口 正确的预测工具。遵循ASAH，亚蛛网膜下腔中的溶血释放大量游离 血红蛋白（HB）。这种有毒的促氧化和促炎性HB和代谢产物（铁，胆红素和胆红素 然后，氧化产物直接与供应大脑的主要动脉进行血管外接触。几个 研究表明，蛛网膜下腔空间内HB浓度的变化（即CSF）趋于 反映简历的演变；虽然，游离HB可能导致此延迟的简历的机制是 理解不佳。 Haptoglobin，Hemopexin，SCD163，转铁蛋白和铁蛋白是主要排毒 结合蛋白质与有毒的游离HB和代谢产物。确实，我们最近在PNA中报告了 Haptoglobin 2-2基因型可能是CV，DCI和长期功能性SAH的独立危险因素 结果，可能是由于从蛛网膜下腔空间中效率低下和自由HB清除的结果。 在这里，我们计划通过详细的机械分析来检验这一假设，并简单地扩展这些结果 使用两种完整的分析方法：1） 采用ITRAQ Nanoflow LC-MS/MS的方法和2）针对分析的公正广泛分析 基于Luminex的多分析物配置平台。包括这种蛋白质组分析方法提供了强大的 这项R21提案的探索性方面最喜欢提供其他公正的新颖途径。 目的1：研究有毒血红蛋白和代谢产物在预测关键ASAH中的生物标志物潜力 临床事件。目标2：研究受保护的血红蛋白和代谢物的生物标志物潜力 在预测关键ASAH临床事件中结合蛋白。 HB，代谢产物和CSF水平配对的血清和CSF水平 保护性结合蛋白将在入院时，然后以6小时的间隔测量 流血。这些临时概况将与简历的事件，严重性和动态相关（上升，峰值， 分辨率），出院时DCI，死亡率和功能结果的发病率，6WK和12MO后出血。我们 已经以标准化的方式收集了大多数此临床数据。在一起，这种方法将 允许候选预后和诊断生物标志物的潜在发展，并可能提供 更好/新颖的机械理解，对阿萨之后的血液清除动力学。因此，我们希望 能够确定这些途径中最大的关键参与者，以实现未来的治疗靶向。