Genetic Architecture of Acute Human Brain Ischemia

描述（由申请人提供）：在缺血性卒中发作后的最初几个小时内，神经功能缺损可能高度不稳定-一些患者自发改善，而另一些患者恶化。这些早期神经系统变化很重要，因为它们对长期结果有很大影响。解释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传播、梗死周围扩散性抑制或出血性转化（HT）。组织纤溶酶原激活剂（tPA）是FDA批准的唯一一种治疗急性缺血性卒中（AIS）的药物，它增加了纤维蛋白溶解和再灌注的可能性;但也增加了HT的机会。我们推测，在急性缺血期间影响致病机制的遗传变异可能会影响AIS后的早期神经功能结局，也可能调节对IV tPA的反应。在这项研究中，我们建议确定与AIS患者（未经治疗或接受IV tPA治疗）的早期神经学结局相关的遗传变异。这些数据将使我们能够找到新的基因/途径和潜在的治疗靶点，可以改善AIS后的结果，并可能提高tPA的疗效。此外，个体的遗传特征可能有一天会为IV 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，我们已经从两个研究中心积累了1000份来自接受tPA治疗的表型AIS患者的样本（世界上最大的此类样本集），这将是 用于基因发现（Discovery Series）。在资助期间，我们将收集额外的3000个样本（复制系列），其中包括tPA治疗和未治疗的患者，以便我们可以确定哪些遗传关联是tPA依赖性的或独立的影响AIS后的早期神经系统结果。我们提出四个目标。目的1：进行全基因组关联研究，检查AIS后早期神经功能改善或恶化。目的2：确定哪些遗传变异可调节与AIS发病机制相关的血浆分析物水平，从而影响早期神经学结局。目的3：为了复制全基因组关联，我们将在AIS患者的独立队列中测试候选变体/基因。目的4：确定与早期结果相关的哪些变体/基因是tPA依赖性的。在这项资助结束时，我们将确定许多影响AIS后早期神经学结果的变异/基因，并将发现以tPA依赖方式影响结果的变异/基因。这些发现将具有诊断和治疗意义。

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.