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，也是成人残疾的主要原因，但目前只有一种获批的中风治疗方法可以达到一小部分患者。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。中风神经科学单位的项目集中于通过人体外周血和组织样本的体内分析，确定与缺血性脑损伤和中风后恢复相关的机制和修饰因素。目前，该实验室正在探索（1）炎症和（2）遗传标志物对卒中风险和结局的临床意义，最终目的是确定生物标志物以及新疗法的分子和遗传靶点。 在过去的一年中，已经确定了许多（1）炎症标志物可以预测中风风险，而新的T细胞亚群的增加与中风复发和死亡显著相关。在妇女健康倡议中，C-反应蛋白、e-选择素、总白色血细胞计数和白细胞介素-6升高可预测中风。在与哈佛公共卫生学院的研究人员合作进行的一项荟萃分析中，发现牙周病是中风风险的预测因素。在我们的实验室中，已经确定了一种新的中风复发和死亡的标志物：T细胞亚群CD 4 + CD 28-的克隆扩增。这些细胞水平升高与中风复发和/或死亡的风险增加2.5倍，在调整年龄，中风严重程度和既往中风史后。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的治疗靶点。我们还确定了一些细胞因子从外周血单核细胞刺激培养中升高的患者相对于对照组，提示激活单核细胞和中性粒细胞中风发作后早期（肿瘤坏死因子和白细胞介素-8）。 在（2）中风基因组学研究中，分析了来自20名患者和20名对照的外周血单核细胞的基因表达谱，并且已经鉴定了113个基因，这些基因在患者和对照之间具有显著差异。验证研究正在进行中，在一个独立的系列10名患者和10名对照。初步结果显示，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图谱。