The role of neutrophils in SAH

中性粒细胞在 SAH 中的作用

• 批准号: 7201784
• 负责人: Jose Javier Provencio
• 金额: $ 16.97万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-02 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7201784
• 关键词: Accounting; Address; Admission activity; Aneurysmal Subarachnoid Hemorrhages; Astrocytes; Biological Assay; Biological Markers; Blood; Blood Circulation; Blood Vessels; Blood donor; Blood specimen; Brain; CXCL1 gene; Cerebral Aneurysm; Cerebral Ischemia; Cerebrospinal Fluid; Cerebrovascular Spasm; Cerebrum; Clinical; Collection; Complex; Complication; Development; Development, Other; Disease; Doctor of Medicine; Dose; Drug Delivery Systems; Enzyme-Linked Immunosorbent Assay; Enzymes; Event; Experimental Models; Flow Cytometry; Functional disorder; Generations; Goals; Head; Hemorrhage; Human; Hydroxyl Radical; IL8 gene; IL8RB gene; Imaging Techniques; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Knockout Mice; Knowledge; Lead; Lipids; Liquid substance; Mass Spectrum Analysis; Mediating; Modeling; Monitor; Morbidity - disease rate; Mus; NADPH Oxidase; Neurologic; Neutrophil Activation; Neutrophil Infiltration; Nitrates; Nitric Oxide; Nitrites; Nucleic Acids; Oxidants; Pathogenesis; Pathway interactions; Patients; Pattern; Peroxidase; Phenylalanine; Physicians; Physiology; Post-Translational Protein Processing; Production; Proteins; Range; Recruitment Activity; Relative (related person); Reporting; Research Personnel; Research Training; Risk; Role; Rupture; Sampling; Scientist; Severities; Source; Stroke; Subarachnoid Hemorrhage; Subarachnoid Space; Superoxides; Syndrome; Testing; Therapeutic; Time; Tissues; Tyrosine; United States; Vascular Endothelial Cell; Vasospasm; Wild Type Mouse; base; career; chemokine; chemokine receptor; cohort; day; disability; information gathering; insight; mortality; mouse model; neutrophil; nitrate; prevent; programs; research study; tool; vasoconstriction

DESCRIPTION (provided by applicant): Subarachnoid hemorrhage is the third leading cause of stroke in the United States but accounts for fifty percent of the mortality and morbidity in cerebral vascular events. The syndrome of delayed cerebral ischemia (vasospasm) is a common, dangerous and poorly understood complication of subarachnoid hemorrhage. Neutrophil infiltration is the predominant early inflammatory response in subarachnoid hemorrhage; however, the role of neutrophils and their products in mediating vasospasm has not been elucidated. Neutrophils make reactive oxidant species (ROS). ROS are implicated in the pathogenesis of vasospasm and are believed to contribute to oxidative injury and nitric oxide (NO) depletion. These are believed to contribute to the blood vessel dysfunction in vasospasm. We propose to test the hypothesis that neutrophil accumulation in the subarachnoid space and selective increase in neutrophil-derived molecular markers of oxidative pathways will correlate with the occurrence of vasospasm after subarachnoid hemorrhage. We plan to investigate this by developing two Specific Aims: 1) We will establish the relationship between neutrophil enrichment in the subarachnoid space, stable molecular markers of distinct oxidative pathways and vasospasm; and 2) we will determine the implications of neutrophil depletion, activation, the inactivation of two neutrophil enzymes, NADPH oxidase and MPO, and the inactivation of the chemokines CXCR2 on the development of vasospasm in a murine model. There is no effective treatment of vasospasm. This proposal will lead to a better understanding of the pathways by which neutrophil infiltration and action may lead to vasospasm. This is relevant because neutrophils and neutrophil chemokines are potential targets for pharmacologic therapy to prevent or treat vasospasm. This proposal and the educational components included form the basis for Dr. Provencio to develop into an independent physician-scientist.

描述（由申请人提供）：蛛网膜下腔出血是美国中风的第三大原因，但占脑血管事件死亡率和发病率的50%。迟发性脑缺血（血管痉挛）综合征是蛛网膜下腔出血的一种常见、危险且鲜为人知的并发症。中性粒细胞浸润是蛛网膜下腔出血的主要早期炎症反应；然而，中性粒细胞及其产物在介导血管痉挛中的作用尚未阐明。中性粒细胞产生活性氧（ROS）。ROS参与血管痉挛的发病机制，并被认为有助于氧化损伤和一氧化氮（NO）的消耗。这些被认为是导致血管痉挛时血管功能障碍的原因。我们提出验证一种假设，即中性粒细胞在蛛网膜下腔的积聚和中性粒细胞衍生的氧化途径分子标志物的选择性增加与蛛网膜下腔出血后血管痉挛的发生有关。我们计划通过以下两个具体目标来对此进行研究：1)我们将建立蛛网膜下腔中性粒细胞富集、不同氧化途径的稳定分子标记和血管痉挛之间的关系；2)我们将在小鼠模型中确定中性粒细胞耗竭、激活、两种中性粒细胞酶（NADPH氧化酶和MPO）失活以及趋化因子CXCR2失活对血管痉挛发展的影响。血管痉挛没有有效的治疗方法。这一建议将有助于更好地理解中性粒细胞浸润和作用可能导致血管痉挛的途径。这是相关的，因为中性粒细胞和中性粒细胞趋化因子是预防或治疗血管痉挛的药物治疗的潜在靶点。这一建议和教育组成部分构成了普罗文西奥博士发展成为一名独立的医生科学家的基础。