Genetic Architecture of Acute Human Brain Ischemia

急性人脑缺血的遗传结构

• 批准号: 8704525
• 负责人: Carlos Cruchaga
• 金额: $ 60.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704525
• 关键词: Accounting; Acute; Affect; Alteplase; Alzheimer' s Disease; Animal Model; Applications Grants; Architecture; Brain Injuries; Brain Ischemia; Candidate Disease Gene; Collateral Circulation; Complex; DNA Resequencing; Data; Data Set; Deterioration; Diagnostic; Diagnostic tests; Exons; FDA approved; Factor XII; Fibrinolysis; Future; Gene Family; Genes; Genetic; Genetic Techniques; Genotype; Grant; Heritability; Hour; Human; IL6 gene; Individual; Infarction; Interferons; Ischemia; Ischemic Stroke; Lead; Link; Lipopolysaccharides; Macroglobulins; Measures; Minor; Mutation; Neurologic; Neurological outcome; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Plasminogen Activator Inhibitor 1; Play; Population; Proteins; Reperfusion Therapy; Risk; Role; Sampling; Series; Site; Spain; Stratification; Stroke; Testing; Therapeutic; Therapeutic Intervention; Thrombus; United States National Institutes of Health; Universities; Variant; Virus Diseases; Washington; acute stress; cohort; disability; gene discovery; genetic analysis; genetic association; genetic profiling; genetic variant; genome wide association study; genome-wide; improved; mortality; neuroimaging; novel; preconditioning; public health relevance; rare variant; response; spreading depression; therapeutic target; trait

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.

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，神经功能缺损可能非常不稳定 - 一些患者会自发改善，而另一些患者则会恶化。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。快速改善的潜在机制包括纤溶/再灌注、侧支循环的募集或内源性神经保护机制；而导致病情恶化的机制包括血栓扩散、梗塞周围扩散抑制或出血转化（HT）。组织纤溶酶原激活剂 (tPA) 是 FDA 唯一批准用于治疗急性缺血性中风 (AIS) 的药物，可增强纤溶和再灌注的可能性；但也增加了HT的机会。我们假设影响急性缺血期间致病机制的遗传变异可能会影响 AIS 后的早期神经系统结果，并且还可能调节对 IV tPA 的反应。在这笔资助中，我们建议鉴定与 AIS 患者（未经治疗或接受 IV tPA 治疗）早期神经系统结果相关的遗传变异。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，从而改善 AIS 后的结果，并可能增强 tPA 疗效。此外，有一天，个体的遗传图谱可能会为 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，我们已从两个中心收集了 1000 个接受 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（发现系列）。在资助期间，我们将额外收集 3000 个样本（复制系列），其中包括接受 tPA 治疗和未治疗的患者，以便我们能够确定哪些遗传关联对 AIS 后的早期神经系统结果是 tPA 依赖性或独立影响。我们提出 4 个目标。目标 1：进行全基因组关联研究，检查 AIS 后早期神经系统的改善或恶化。目标 2：确定哪些基因变异可调节与 AIS 发病机制相关的血浆分析物水平，从而影响早期神经系统结果。目标 3：为了复制全基因组关联，我们将在独立的 AIS 患者队列中测试候选变异/基因。目标 4：确定哪些与早期结果相关的变异/基因是 tPA 依赖性的。在本次资助结束时，我们将鉴定出许多影响 AIS 后早期神经系统结果的变异/基因，并且还将发现以 tPA 依赖性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。