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.

急性动脉瘤性蛛网膜下腔出血(Asah)是一种复杂且多方面的疾病。 从几天到几周。由于脑血管痉挛(CV)、迟发性脑缺血 (DCI)和糟糕的SAH结果，一直没有成功的努力来建立治疗 减少脑血管意外的发生率。确定早期的易感遗传因素和/或生物标记物 CV值的预测可作为ASAH患者重症监护管理的一种临床有用工具。 我们知道脑循环在蛛网膜下腔出血后7-9天达到峰值，所以我们有一个独特的治疗窗口--只要我们有 正确的预测工具。在ASAH之后，蛛网膜下腔的溶血释放出大量的游离 血红蛋白(Hb)。这种有毒的促氧化和促炎的Hb和代谢物(铁、胆红素和胆红素 氧化产物)然后直接与供应大脑的主要动脉在血管外接触。几个 研究表明，蛛网膜下腔(即脑脊液)内Hb浓度的变化倾向于 以反映心血管的演变；尽管，游离Hb可能导致这种延迟的心血管的机制是 人们对此知之甚少。结合珠蛋白、血凝素、sCD163、转铁蛋白和铁蛋白是主要的解毒物质。 与有毒的游离Hb和代谢物结合的蛋白质。事实上，我们最近在PNAS上报告说 结合珠蛋白2-2基因可能是心血管疾病、DCI和长期功能不良的SAH的独立危险因素 结果，可能是由于无效的管理和清除蛛网膜下腔中的游离Hb所致。 在这里，我们计划通过详细的机理分析来检验这一假设，并同时扩展这些结果 使用两种互补的分析方法预测和诊断生物标记物的发展：1) 使用基于iTRAQ Nanoflow LC-MS/MS的方法进行无偏见的广泛分析，以及2)在 基于Luminex的多分析配置文件平台。包括这种蛋白质组图谱方法提供了一种强大的 R21提案的探索性方面，最有可能提供额外的、公正的新途径。 目的1：探讨毒性血红蛋白及其代谢产物在预测关键ASAH中的生物标志物潜力 临床事件。目的2：研究保护性血红蛋白及其代谢物的生物标志物潜力。 结合蛋白在预测关键ASAH临床事件中的作用。配对的血清和脑脊液水平的Hb、代谢物和 保护性结合蛋白将在入院时和之后每隔6小时检测一次，最长为14天- 流血。这些时间分布将与心血管疾病的发生率、严重性和动态(上升、峰值、 出院时、出院后6周和12个月时的DCI发生率、死亡率和功能结果。我们 已经以标准化的方式收集了这些临床数据的大部分。总而言之，这种方法将 允许潜在地开发候选预后和诊断生物标记物，并可能提供 对ASAH后血液清除动力学的更好/新的机制理解。因此，我们希望 能够确定这些途径中最合适的关键参与者，为未来的治疗靶向。