Mechanisms and modifying factors of ischemic brain injur

缺血性脑损伤的机制及影响因素

• 批准号: 6843283
• 负责人: Alison E Baird
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6843283
• 关键词: biomarker; brain imaging /visualization /scanning; brain injury; cerebral ischemia /hypoxia; cytokine; functional /structural genomics; functional ability; gene expression; genetic susceptibility; human subject; inflammation; lymphocyte; magnetic resonance imaging; microarray technology; monocyte; neutrophil; stroke

While stroke is the third leading cause of death and the leading cause of adult disability, there is only one approved stroke therapy at present that reaches a small percentage of patients. One major factor for the lack of stroke treatments is the lack of knowledge about stroke pathophysiology. The projects of the Stroke Neuroscience Unit are focused on determining the mechanisms and modifying factors associated with ischemic brain injury and with recovery after stroke, by the in vivo analysis of human peripheral blood and tissue samples. Currently the laboratory is exploring the clinical significance of (1) inflammatory and (2) genetic markers on stroke risk and outcome, the ultimate aim being to identify biomarkers and molecular and genetic targets for novel therapies. Over the past year, a number of (1) inflammatory markers have been identified that are predictive of stroke risk, while an increase in a novel T cell subset has been found to be significantly associated with stroke recurrence and death. In the Women's Health Initiative, elevated C-reactive protein, e-selectin, total white blood cell count and interleukin-6 were predictive of stroke. Periodontal disease was found to be predictive of stroke risk in a meta-analysis performed in collaboration with investigators at the Harvard School of Public Health. In our lab, a novel marker for stroke recurrence and death has been identified: clonal expansion of a T cell subset, CD4+CD28-. Elevated levels of these cells are associated with a 2.5 times greater risk of stroke recurrence and/or death at one year, after adjustment for age, stroke severity and a history of prior stroke. These cells may serve as a biomarker and potential therapeutic target for preventing stroke recurrence and death. We have also identified a number of cytokines from peripheral blood mononuclear cells stimulated in culture that are elevated in patients relative to controls, suggesting activation of monocytes and neutrophils early after stroke onset (tumor necrosis factor and interleukin-8). In the (2) stroke genomics studies, the gene expression profile of peripheral blood mononuclear cells from 20 patients and 20 controls has been analyzed and 113 genes have been identified that are significantly different between patients and controls. Validation studies are in progress in an independent series of 10 patients and 10 controls. Initial results are showing that the training dataset shows good discrimination between patients and controls. Studies are ongoing and being extended to the genomic profile associated with stroke recovery.

虽然中风是第三大死亡原因和成人残疾的主要原因，但目前只有一种批准的中风治疗方法可以覆盖一小部分患者。缺乏中风治疗的一个主要因素是缺乏对中风病理生理学的了解。中风神经科学部门的项目重点是通过对人体外周血和组织样本的体内分析来确定与缺血性脑损伤以及中风后恢复相关的机制和改变因素。目前，该实验室正在探索（1）炎症和（2）遗传标记对中风风险和结果的临床意义，最终目标是确定新疗法的生物标记以及分子和遗传靶点。 在过去的一年里，已经确定了许多 (1) 炎症标记物可以预测中风风险，同时发现一种新型 T 细胞亚群的增加与中风复发和死亡显着相关。在妇女健康倡议中，C 反应蛋白、e-选择素、白细胞总数和白细胞介素 6 升高可预测中风。与哈佛大学公共卫生学院的研究人员合作进行的荟萃分析发现，牙周病可以预测中风风险。在我们的实验室中，已经确定了一种中风复发和死亡的新标志物：T 细胞亚群 CD4+CD28- 的克隆扩增。在调整年龄、中风严重程度和既往中风病史后，这些细胞的水平升高与一年内中风复发和/或死亡的风险增加 2.5 倍相关。这些细胞可以作为预防中风复发和死亡的生物标志物和潜在治疗靶点。我们还从培养物中刺激的外周血单核细胞中发现了许多细胞因子，这些细胞因子在患者中相对于对照组升高，表明中风发作后早期单核细胞和中性粒细胞的激活（肿瘤坏死因子和白介素-8）。 在(2)中风基因组学研究中，分析了20名患者和20名对照者的外周血单核细胞的基因表达谱，并鉴定了患者和对照者之间显着不同的113个基因。一项由 10 名患者和 10 名对照者组成的独立系列验证研究正在进行中。初步结果表明，训练数据集在患者和对照组之间显示出良好的区分度。研究正在进行中，并扩展到与中风恢复相关的基因组谱。