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.

尽管中风是死亡的第三大主要原因，也是成人残疾的主要原因，但目前只有一种批准的中风疗法达到了一小部分患者。缺乏中风治疗的主要因素是缺乏有关中风病理生理学的知识。中风神经科学单元的项目着重于确定与缺血性脑损伤相关的机制和修饰因素，并通过对人外周血和组织样本的体内分析进行的体内分析。目前，该实验室正在探索（1）炎症性和（2）对中风风险和结果的遗传标记的临床意义，最终目的是鉴定生物标志物以及新型疗法的分子和遗传靶标。 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，而新型T细胞子集的增加与中风复发和死亡显着相关。在女性健康计划中，C反应蛋白，E-选择蛋白，总白细胞计数和白介素-6是中风的预测。发现牙周疾病可以预测与哈佛公共卫生学院的研究人员合作进行的荟萃分析中的中风风险。在我们的实验室中，已经确定了一种新颖的中风复发和死亡标记：T细胞子集的克隆扩张，CD4+CD28-。这些细胞的水平升高与对年龄，中风严重程度和先前中风病史的调整后一年的中风复发和/或死亡的风险高2.5倍。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标。我们还鉴定了来自患者相对于对照组的培养中刺激的外周血单核细胞中的许多细胞因子，这表明中风发作后早期激活单核细胞和中性粒细胞（肿瘤坏死因子和白介素-8）。 在（2）中风基因组学研究中，已经分析了来自20例患者和20例对照的外周血单核细胞的基因表达谱图，并且已经鉴定出了113个基因，这些基因在患者和对照组之间有显着差异。验证研究正在进行10名患者和10个对照组的独立系列中。最初的结果表明，训练数据集在患者和对照组之间显示出良好的歧视。研究正在进行中，并扩展到与中风恢复相关的基因组谱。