Molecular Biology of Stroke in Humans

描述（由申请人提供）：本提案将检查血液中细胞对人类缺血性卒中的分子反应。该建议是基于我们的初步数据，显示特定的基因表达谱在血液中的大血管动脉粥样硬化，心源性栓塞和腔隙性中风的原因。这些特征部分是为了预测30%的中风患者，他们的中风原因未知（隐源性）。使用这些特征，17%的隐源性卒中患者被预测为大血管动脉粥样硬化，41%被预测为心源性栓塞，27%的心源性栓塞性卒中被预测为阵发性房颤（PAF）。这些发现很重要，因为它们影响了治疗的使用-抗凝血剂如香豆素用于心源性栓塞，血管手术和抗血小板药物用于大血管动脉粥样硬化，抗血小板药物用于腔隙性卒中。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卒中表达谱中的基因来预测缺血性卒中的原因，灵敏度和特异性>90%。(2)对于目标#1中使用PCR阵列预测因PAF而发生心源性卒中的隐源性卒中患者，证明他们在卒中后心脏监测期间患有PAF。(3)在年龄、性别、种族和血管风险因素匹配的一半患者中，从分离的PMN和单核细胞中获得缺血性卒中的大血管、心源性栓塞和腔隙性病因的基因表达谱，并进行多重比较校正。表明这些谱预测缺血性脑卒中病因的下半期脑卒中患者的敏感性和特异性均>90%。 第一个目标将是首次使用我们以前的全血研究中的基因表达谱，在本研究中使用PCR阵列在一个单独的独立队列中预测中风的原因。第二个目标是预测哪些隐源性中风是由PAF引起的，并将使用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，以评估这些细胞在中风的不同原因中的作用。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的几天内获得结果。隐源性中风的基因谱将加速最合适的治疗方法的提供，并使隐源性中风的原因的进一步评估更快，更便宜和更成功。

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.