Biomarkers of Vasospasm and Outcome following Subarachnoid Hemorrhage

描述（由申请人提供）：蛛网膜下腔出血（SAH）每年影响超过30,000名美国人，是65岁及以下人群中风相关潜在生命年损失的主要原因之一。尽管SAH患者的重症监护取得了进展，但超过一半的SAH幸存者仍然存在严重的残疾。血管痉挛可在高达70%的SAH幸存者中发生，是SAH后额外脑损伤和残疾的最重要原因之一。目前，没有诊断测试可以确定SAH患者有发生血管痉挛的风险。血管痉挛的诊断和治疗是高风险的，往往是侵入性的。SAH后血管痉挛和继发性脑损伤和残疾的原因尚不完全清楚。在这项研究中，我们检查了从SAH受试者采集的血液和脑脊液样本中提取的特定分子生物标志物，以了解它们在引起SAH后血管痉挛和继发性脑损伤中的潜在作用。我们将招募200名SAH患者，储存他们的血液和脑脊液样本，并使用先进的分子技术分析和检测潜在的新型分子生物标志物。我们的第一个目的是检查血管造影上血管痉挛与白细胞释放基质金属蛋白酶（MMPs）之间的关系，MMPs可以将内皮素-1切割成碎片，随后引起脑动脉痉挛。我们的第二个目标是将SAH相关的残疾与白细胞释放MMPs及其与细胞因子、血浆凝胶和肌动蛋白分子的相互作用联系起来，这些分子介导了SAH等危重疾病的炎症反应。最后，我们将使用前两个目标生成的数据建立一个数学模型，旨在帮助医生识别SAH患者发生血管痉挛和进一步残疾的高风险。我们希望这项研究的结果能够促进我们对SAH中导致血管痉挛和继发性脑损伤的重要分子机制的理解。我们的工作将为发现新的无创床边检查奠定基础，这些检查可以更好地诊断和预测血管痉挛以及SAH后有更大残疾风险的患者。最终，我们希望对SAH后血管痉挛和继发性脑损伤分子机制的理解将有助于我们找到新的治疗方法，提高SAH患者的生存率并减少其残疾。

DESCRIPTION (provided by applicant): Subarachnoid hemorrhage (SAH) affects over 30,000 Americans per year and is one of the major causes of stroke-related potential life-years lost in people age 65 and younger. Despite advances in critical care for SAH patients, more than half of SAH survivors still live with significant disability. Vasospasm, which can occur in up to 70% of SAH survivors, is one of the most important causes for additional brain injury and disability after SAH. Currently, there are no diagnostic tests that can identify SAH patients at risk for developing vasospasm. The diagnosis and treatment of vasospasm are high-risk and often invasive. The causes of vasospasm and secondary brain injury and disability following SAH remain incompletely understood. In this study, we examine specific molecular biomarkers from blood and cerebrospinal fluid samples collected from SAH subjects in order to understand their potential role in causing vasospasm and secondary brain injury following SAH. We will recruit 200 patients with SAH, bank their available blood and cerebrospinal fluid samples, and use advanced molecular techniques to analyze and detect potentially novel molecular biomarkers. Our first aim is to examine the relationship between vasospasm seen on angiogram with white blood cells' release of matrix metalloproteinases (MMPs) which can cleave endothelin-1 into fragments that can subsequently cause spasm of cerebral arteries. Our second aim is to correlate SAH-related disability with white blood cells' release of MMPs and their interactions with cytokines, plasma gelsolin, and actin - molecules that mediate inflammatory reaction in critical illness such as SAH. Finally, we will use the data generated through our first 2 aims to build a mathematical model aimed to help physicians identify SAH patients who are at high risk for developing vasospasm and further disability. We hope results of this study will advance our understanding on important molecular mechanisms that lead to vasospasm and to secondary brain injuries in SAH. Our work will lay the foundation for potential discovery of new non-invasive bedside tests that can better diagnose and predict vasospasm and patients at risk for greater disability following SAH. Ultimately, we hope advances in understanding of molecular mechanisms of vasospasm and secondary brain injury following SAH will help us identify new therapies that may improve survival and reduce disability in SAH patients.