Molecular Biology of Stroke in Humans

人类中风的分子生物学

• 批准号: 8696896
• 负责人: FRANK R SHARP
• 金额: $ 61.61万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696896
• 关键词: Accounting; Affect; Age; Anticoagulants; Anticoagulation; Atherosclerosis; Atrial Fibrillation; Blood; Blood Cells; Blood Platelets; Blood Vessels; Brain hemorrhage; Cardiac; Cells; Coagulation Process; Data; Diagnosis; Etiology; Evaluation; Future; Gender; Gene Expression; Genes; Genome; Human; Incidence; Inflammatory; Ischemic Stroke; Messenger RNA; Molecular; Molecular Biology; Molecular Profiling; Molecular Target; Monitor; Pathogenesis; Patients; Prevention; Procedures; Race; Rattus; Recurrence; Risk Factors; Role; Sensitivity and Specificity; Speed; Stroke; Stroke prevention; Technology; Tube; United States National Institutes of Health; Waran; Whole Blood; base; cohort; improved; mRNA Expression; monocyte; response; single molecule

DESCRIPTION (provided by applicant): This proposal will examine the molecular response of cells in blood to ischemic stroke in humans. The proposal is based upon our preliminary data showing specific gene expression profiles in blood for large vessel atherosclerotic, cardioembolic and lacunar causes of stroke. These profiles were derived in part to predict the 30% of stroke patients who have unknown (cryptogenic) causes of their strokes. Using these profiles, 17% of cryptogenic stroke patients were predicted to have large vessel atherosclerosis, 41% were predicted to be cardioembolic, and 27% of the cardioembolic strokes were predicted to have paroxysmal atrial fibrillation (PAF). These findings are important since they affect what treatment is used - anticoagulants like coumadin for cardioembolic causes, vascular procedures and anti-platelet agents for large vessel atherosclerotic causes, and anti-platelet agents for lacunar stroke. Based upon these data we propose the following aims. (1) Use PCR arrays and the genes from our expression profiles for large vessel atherosclerotic, cardioembolic and lacunar stroke to predict the causes of ischemic strokes in this study using whole blood with >90% sensitivity and specificity. (2) For the cryptogenic stroke patients predicted to have cardioembolic strokes due to PAF using PCR arrays in Aim #1, demonstrate they have PAF during cardiac monitoring following their stroke. (3) Derive gene expression profiles from isolated PMNs and monocytes for large vessel, cardioembolic and lacunar causes of ischemic stroke in one half of the patients matched for age, gender, race and vascular risk factors and corrected for multiple comparisons. Show that these profiles predict the causes of ischemic stroke in the second half of the stroke patients with >90% sensitivity and specificity. The first aim will be the first to use the gene expression profiles from our previous studies of whole blood to predict the causes of stroke using PCR arrays in a separate independent cohort in this study. The second aim predicts which cryptogenic strokes are caused by PAF and will confirm these using cardiac monitoring. The studies of PMNs and monocytes will begin to assess the roles of these cells in different causes of stroke. Predicting the causes of cryptogenic strokes has the potential to soon decrease the incidence of recurrent ischemic strokes since the results can be obtained within days of the stroke using current PCR array technology. The gene profiles for cryptogenic stroke will speed delivery of the most appropriate treatments and make further evaluations of the causes of the cryptogenic strokes quicker, less expensive and more successful.

描述（由申请人提供）：该提案将检查血液中细胞对人类缺血性中风的分子反应。该提议基于我们的初步数据，该数据显示了血液中大血管动脉粥样硬化、心源性栓塞和腔隙性中风原因的特定基因表达谱。这些概况的部分推导是为了预测 30% 的中风患者中风原因不明（原因不明）。利用这些资料，17% 的隐源性中风患者预计患有大血管动脉粥样硬化，41% 预计患有心源性栓塞，27% 的心源性中风患者预计患有阵发性心房颤动 (PAF)。这些发现很重要，因为它们影响了治疗的使用——抗凝剂如香豆素用于心源性栓塞原因，血管手术和抗血小板药物用于大血管动脉粥样硬化原因，以及抗血小板药物用于腔隙性中风。根据这些数据，我们提出以下目标。 (1) 在本研究中，使用全血，使用 PCR 阵列和我们的大血管动脉粥样硬化、心源性栓塞和腔隙性中风表达谱中的基因来预测缺血性中风的原因，灵敏度和特异性 >90%。 (2) 对于目标 #1 中使用 PCR 阵列预测因 PAF 导致的隐源性中风患者，在中风后的心脏监测期间证明他们患有 PAF。 (3) 从分离的中性粒细胞和单核细胞中获得与年龄、性别、种族和血管危险因素相匹配的一半患者中缺血性中风的大血管、心源性栓塞和腔隙性病因的基因表达谱，并针对多重比较进行校正。表明这些概况预测中风患者后半程缺血性中风的原因的敏感性和特异性 >90%。 第一个目标是第一个使用我们之前全血研究的基因表达谱来预测中风的原因，在本研究的一个单独的独立队列中使用 PCR 阵列。第二个目标是预测哪些隐源性中风是由 PAF 引起的，并将通过心脏监测来确认这些。对中性粒细胞和单核细胞的研究将开始评估这些细胞在不同原因的中风中的作用。预测隐源性中风的原因有可能很快降低复发性缺血性中风的发生率，因为使用当前的 PCR 阵列技术可以在中风发生后几天内获得结果。隐源性中风的基因谱将加快提供最合适的治疗，并使对隐源性中风病因的进一步评估更快、更便宜、更成功。