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

基本信息

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
项目类别：
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

项目摘要

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，其表现如下由于脑血管痉挛（CV）、迟发性脑缺血之间的这种关系。 (DCI) 和 SAH 结局不佳，人们一直在努力建立治疗方法，但没有成功降低 CV 的发病率。 CV 预测将成为 aSAH 患者重症监护管理中临床上有用的工具。知道 CV 在 SAH 后 7-9 天达到峰值，我们在这里有一个独特的治疗窗口——只要我们正确的预测工具 aSAH 后，蛛网膜下腔发生溶血，释放大量游离物质。血红蛋白 (Hb)，这种有毒的促氧化和促炎 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进行血管外接触。研究表明，蛛网膜下腔（即 CSF）内 Hb 浓度的变化倾向于然而，为了反映 CV 的演变，游离 Hb 可能导致 CV 延迟的机制是结合珠蛋白、血红蛋白、sCD163、转铁蛋白和铁蛋白是一些主要的解毒剂。事实上，我们最近在 PNAS 上报道了这一点。触珠蛋白 2-2 基因型可能是 CV、DCI 和长期功能性 SAH 不良的独立危险因素结果，可能是由于蛛网膜下腔游离血红蛋白管理和清除不力造成的。在这里，我们计划通过详细的机制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开发预后和诊断生物标志物：1) 使用基于 iTRAQ 纳流 LC-MS/MS 的方法进行无偏见的广泛分析，以及 2) 在基于 luminex 的多分析物分析平台包含此类蛋白质组分析方法，提供了强大的功能。 R21 提案的探索性方面最有可能提供额外的公正的新途径。目标 1：研究有毒血红蛋白和代谢物在预测关键 aSAH 中的生物标志物潜力目标 2：研究保护性血红蛋白和代谢物的生物标志物潜力。结合蛋白预测关键的 aSAH 临床事件。将在入院时以及此后每隔 6 小时测量保护性结合蛋白，持续时间长达 14 天。这些时间曲线将与 CV 的发生率、严重程度和动态（上升、峰值、分辨率）、DCI 发生率、死亡率和出院时、出血后 6 周和 12 个月的功能结果。已经以标准化方式收集了大部分临床数据。允许候选预后和诊断生物标志物的潜在开发，并可能提供对 aSAH 后血液清除动态的更好/新颖的机制理解因此，我们期望能够识别这些途径中最合适的关键参与者，以实现未来的治疗目标。