Molecular Biology of Stroke in Humans

人类中风的分子生物学

• 批准号: 8487467
• 负责人: FRANK R SHARP
• 金额: $ 60.05万
• 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/8487467
• 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。该提案基于我们的初步数据，显示了大型血管硬化，心脏肌肉和lacunar造成的特定基因表达谱。这些轮廓的部分是为了预测其中风原因未知（隐态性）原因的30％。使用这些特征，预计有17％的隐性卒中患者患有大血管硬化，预计有41％是心脏核心的，预计有27％的心栓塞性中风被预测为阵发性纤维化性心房纤维化（PAF）。这些发现很重要，因为它们会影响使用的治疗方法 - 抗肌动蛋白等抗核因素，用于心脏符号原因，血管手术和抗位于大血管性动脉粥样硬化原因的抗植物药物，以及用于lacunar中风的抗植物药物。基于这些数据，我们提出以下目的。 （1）将PCR阵列和我们表达谱的基因用于大血管性动脉粥样硬化，心脏栓塞和lacunar卒中，以预测本研究中使用具有> 90％敏感性和特异性的全血的缺血性中风的原因。 （2）对于aim＃1中使用PCR阵列的PCR阵列，预测的隐态性中风患者预测将具有心脏符号中风，这表明他们在中风后在心脏监测过程中具有PAF。 （3）从孤立的PMN和单核细胞中得出基因表达谱，用于大容器，心脏宿主和lacunar原因，导致缺血性中风的病因，其中一半的患者与年龄，性别，种族和血管危险因素相匹配，并纠正了多次比较。表明这些曲线预测了下半部分中的缺血性中风的原因，其敏感性和特异性> 90％。 第一个目的是第一个在本研究中使用PCR阵列中使用PCR阵列中的全血的基因表达曲线来预测中风的原因。第二个目的预测哪些隐源性中风是由PAF引起的，并将使用心脏监测确认这些中风。 PMN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原因中的作用。预测隐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。隐性中风的基因概况将加快最合适的治疗方法，并进一步评估隐秘性中风的原因，更快，更便宜，更成功。