The role of neutrophils in SAH

中性粒细胞在 SAH 中的作用

基本信息

批准号：
7535499
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
项目类别：
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/7535499
关键词：
Accounting Address Admission activity Aneurysmal Subarachnoid Hemorrhages Astrocytes Biological Assay 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 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 Peroxidases Phenylalanine Physicians Physiology Post-Translational Protein Processing Production Proteins 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 disability effective therapy inflammatory marker information gathering insight molecular marker mortality mouse model neutrophil prevent programs research study tool vasoconstriction

项目摘要

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 proposal to test the hypothesisthat 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.

蛛网膜下腔出血是美国中风的第三主要原因，但占五十个脑血管事件中死亡率和发病率的百分比。延迟大脑的综合征缺血（血管痉挛）是一种常见，危险且知识不足的蛛网膜炎并发症出血。中性粒细胞浸润是蛛网膜下腔中的主要早期炎症反应出血；但是，中性粒细胞及其产物在介导血管痉挛中的作用并非阐明。中性粒细胞使反应性氧化剂（ROS）。 ROS与血管痉挛，被认为有助于氧化损伤和一氧化氮（NO）耗竭。这些都是据信导致血管痉挛的血管功能障碍。我们建议检验假设中性粒细胞在亚蛛网膜下腔中的积累和中性粒细胞衍生的分子的选择性增加氧化途径的标志物将与亚蛛网膜下腔后的血管痉挛发生相关出血。我们计划通过开发两个具体目标来调查这一点：1）我们将建立中性粒细胞富集在亚蛛网膜下腔中的关系，稳定的分子标志物不同氧化途径和血管痉挛； 2）我们将确定中性粒细胞耗尽的含义，激活，两种中性粒细胞酶，NADPH氧化酶和MPO的失活，以及灭活趋化因子CXCR2关于鼠模型中血管痉挛的发展。没有有效的治疗血管痉挛。该建议将使中性粒细胞更好地理解浸润和作用可能导致血管痉挛。这很重要，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理治疗的潜在靶标。这个建议教育组成部分包括Provencio博士发展成为独立的基础医师科学家。