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.

虽然中风是导致死亡的第三大原因，也是导致成人残疾的主要原因，但目前只有一种经批准的中风治疗方法能惠及一小部分患者。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。脑卒中神经科学组的项目主要是通过对人外周血和组织样本的体内分析，确定与缺血性脑损伤和脑卒中后恢复相关的机制和调节因素。目前，该实验室正在探索(1)炎症和(2)遗传标记物对中风风险和预后的临床意义，最终目的是确定生物标记物以及新疗法的分子和遗传靶点。