Molecular Biology of Stroke in Humans

描述(由申请人提供)：这项提案将研究人类血液中细胞对缺血性中风的分子反应。这项建议是基于我们的初步数据，该数据显示了大血管动脉粥样硬化、心源性栓塞症和腔隙卒中原因在血液中的特定基因表达谱。这些资料的得出部分是为了预测30%的中风患者的中风原因不明(不明原因)。使用这些资料，17%的不明原因中风患者被预测为大血管动脉粥样硬化，41%被预测为心源性中风，27%的心源性中风患者被预测为阵发性心房颤动(PAF)。这些发现很重要，因为它们影响到所使用的治疗方法--用于心源性栓塞症的香豆素等抗凝剂，用于大血管动脉粥样硬化原因的血管手术和抗血小板药物，以及用于腔隙性中风的抗血小板药物。基于这些数据，我们提出了以下目标。(1)使用聚合酶链式反应阵列和我们的大血管动脉粥样硬化、心脏栓塞症和腔隙性卒中的表达谱中的基因来预测缺血性卒中的原因，在这项研究中，使用全血具有90%的敏感性和特异性。(2)对于在AIM#1中使用PCR阵列预测因PAF而发生心脏栓塞性中风的隐源性中风患者，证明他们在卒中后的心脏监测中存在PAF。(3)在年龄、性别、种族和血管危险因素匹配的一半患者中，从分离的中性粒细胞和单核细胞中获得缺血性中风的大血管、心栓性和腔隙原因的基因表达谱，并进行多重比较校正。结果表明，这些图谱预测中风后半期患者中缺血性中风的病因具有90%的敏感性和特异性。第一个目标是首次使用我们之前对全血进行的研究中的基因表达谱来预测中风的原因，在这项研究中，使用独立队列中的聚合酶链式反应阵列。第二个目的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证实这些。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中风病因中的作用。预测隐源性中风的原因有可能很快降低复发的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后几天内获得结果。隐源性中风的基因图谱将加快提供最合适的治疗方法，并使进一步评估隐源性中风的原因更快、更便宜、更成功。 公共卫生相关性：这项研究检查了人类缺血性中风后血液中的全基因组反应，并确定了区分不同原因的缺血性中风的基因表达谱。不同原因的缺血性卒中的基因图谱被用来预测由阵发性房颤(PAF)引起的心脏栓塞引起的隐源性(未知原因)卒中，这一点已通过持续的心脏监测得到证实。这些研究很重要，因为它们将确定是否将抗凝、血管手术或抗血小板药物用于不明原因中风患者的二级中风预防。

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. PUBLIC HEALTH RELEVANCE: This study examines whole genome responses in blood of humans following ischemic stroke and identifies gene expression profiles that discriminate different causes of ischemic stroke from each other. The gene profiles for different causes of ischemic stroke are used to predict cryptogenic (no known cause) strokes caused by cardioembolism due to paroxysmal atrial fibrillation (PAF) which are confirmed using continuous cardiac monitoring. The studies are important because they will determine whether anticoagulation, vascular procedures or anti-platelet agents are used for secondary stroke prevention in cryptogenic stroke patients.