Genetic Architecture of Acute Human Brain Ischemia

描述（由申请人提供）：在缺血性中风发作后的最初几个小时内，神经功能障碍可能是高度不稳定的——一些患者自发改善，而另一些患者则恶化。这些早期的神经变化很重要，因为它们对长期的结果有很大的影响。快速改善的潜在机制包括纤维蛋白溶解/再灌注、侧支循环募集或内源性神经保护机制；而导致恶化的机制包括血栓扩散、梗死周围扩散抑制或出血性转化（HT）。组织纤溶酶原激活剂（tPA）是fda批准的唯一用于治疗急性缺血性卒中（AIS）的药物，可增强纤维蛋白溶解和再灌注的可能性；但也增加了患HT的几率。我们假设在急性缺血期间影响致病机制的遗传变异可能影响AIS后的早期神经预后，也可能调节对静脉注射tPA的反应。在这项资助中，我们建议鉴定与AIS患者（未经治疗或接受静脉注射tPA治疗）早期神经系统预后相关的遗传变异。这些数据将使我们能够发现新的基因/途径和潜在的治疗靶点，这些靶点可以改善AIS后的预后，并可能提高tPA的疗效。此外，一个人的遗传特征可能有一天会为静脉注射tPA治疗提供个性化的风险分层，这可能会指导治疗决策。目前，我们已经从这两个地点积累了1000份来自经tPA治疗的表现型AIS患者的样本（世界上最大的此类样本集），这将是

DESCRIPTION (provided by applicant): During the first hours after ischemic stroke onset, neurological deficits can be highly unstable - some patients spontaneously improve while others deteriorate. These early neurological changes are important because they have a large influence on long-term outcome. Potential mechanisms accounting for rapid improvement include fibrinolysis/ reperfusion, recruitment of collateral circulation, or endogenous neuroprotective mechanisms; while mechanisms leading to deterioration include thrombus propagation, peri-infarct spreading depression, or hemorrhagic transformation (HT). Tissue plasminogen activator (tPA), the only FDA-approved drug for the treatment of acute ischemic stroke (AIS), enhances the likelihood of fibrinolysis and reperfusion; but also increases the chances of HT. We hypothesize that genetic variant that affect pathogenic mechanism during acute ischemia may influence early neurological outcomes after AIS, and may also modulate response to IV tPA. In this grant, we propose to identify genetic variants associated with early neurological outcome in AIS patients (untreated or treated with IV tPA). These data will permit us to find novel genes/pathways and potential therapeutic targets that could improve outcome after AIS, and perhaps enhance tPA efficacy. Further, an individual's genetic profile may one day provide personalized risk stratification for treatment with IV tPA, which may guide therapeutic decisions. Currently, we have accumulated 1000 samples from phenotyped AIS patients treated with tPA from both sites (the largest such sample set in the world), which will be used for gene discovery (Discovery Series). During the grant period, we will collect an additional 3000 samples (Replication Series), which will include both tPA-treated and untreated patients so that we can determine which genetic associations are tPA-dependent or independent influences on early neurological outcomes after AIS. We propose 4 aims. Aim 1: To perform genome-wide association studies, examining early neurological improvement or deterioration after AIS. Aim 2: To determine which genetic variants that modulate levels of plasma analytes relevant to AIS pathogenesis influence early neurological outcomes. Aim 3: To replicate genome-wide associations, we will test candidate variants/genes in an independent cohort of AIS patients. And Aim 4: To determine which variants/genes associated with early outcome are tPA-dependent. At the conclusion of this grant, we will identify many variants/genes that influence early neurological outcome after AIS, and will also find variants/genes that influence outcome in a tPA-dependent manner. These findings will have both diagnostic and therapeutic implications.