Genetic Architecture of Cerebral Edema after Stroke

项目摘要 脑水肿是神经功能恶化的主要原因，也是院内死亡的主要原因 中风后这种病理性的水积聚导致脑体积的增加， 大脑半球中风后的症状这种脑肿胀不仅会增加脑疝的风险， 中风恢复和梗塞增长一样多。然而，关键的生物因素和分子机制 介导脑水肿形成的神经系统仍然不清楚。这种知识差距阻碍了发展 有针对性的干预措施，以减轻水肿的后果，在不同的条件，如脑外伤， 肿瘤和出血性以及缺血性中风。患者之间存在显著差异，其中一些 表现出恶性水肿，而其他患者尽管中风大小和严重程度相似，但无至轻度肿胀。的 该提案的中心目标是将成像与遗传学相结合，以确定关键的生物途径， 介导的脑水肿。我们将在NINDS资助的一个由3，506名患者组成的 中风遗传学研究（GENISIS）和1,000人参加了ERA-NET NEURON资助的研究（iBioStroke）。 我们将应用自动分析管道来获得水肿的定量多维测量 严重性。我们的主要生物标志物是脑脊液置换（ΔCSF），它作为 中风后肿胀的体积。然而，我们还将测量大脑半球的CSF比率， 和损伤性水吸收作为额外的水肿表型。我们将模拟水肿形成（与时间相关 从中风发作）来评估生物因素，如年龄，性别，血糖，血压， 和肾功能，影响水肿形成。我们的中心假设是水肿的患者间差异 形成可以与靶向临床因素如高血糖症和信息遗传因素相关联。 差异我们的初步数据表明ΔCSF具有显著的遗传成分。具体目标 1旨在量化关键临床因素（如高血糖和血压）与水肿的关系 阵我们将利用基因组数据进一步剖析哪些因素是水肿形成的原因， 使用孟德尔随机化。我们还将量化水肿和出血性转化对 中风恢复具体目标2将确定与中风后脑水肿相关的基因和途径。它 将采用全基因组关联（GWAS）方法，在这个大型队列中进行多种水肿表型。 我们将使用功能注释工具进一步优先考虑基因和途径。Specific Aim 3将剖析共享 与水肿特异性损伤机制，通过分析水肿与出血性 转化、白色物质损伤和小血管病变。它将利用现有的大型数据集， Aim 2的基因发现能力。一旦完成，这项工作将提供第一个全面的图片， 中风后脑水肿的遗传结构，并提供公正的，新的见解， 可以为药物发现提供信息的靶点。

PROJECT SUMMARY Cerebral edema is a major contributor to neurological deterioration and the leading cause of in-hospital death after stroke. This pathologic water accumulation results in an increase in brain volume that can be measured after most hemispheric strokes. This brain swelling not only raises the risk of cerebral herniation but also impairs stroke recovery as much as infarct growth does. However, the key biologic factors and molecular mechanisms that mediate formation of cerebral edema remain poorly defined. This knowledge gap has hindered development of targeted interventions to mitigate the consequences of edema in conditions as diverse as brain trauma, tumors, and hemorrhagic as well as ischemic strokes. There is significant variability between patients, with some exhibiting malignant edema and others with none to mild swelling despite similar stroke sizes and severities. The central objective of this proposal is to integrate imaging with genetics to identify key biologic pathways and mediators implicated in cerebral edema. We will acquire serial CT scans from 3,506 patients in an NINDS-funded stroke genetics study (GENISIS) and 1,000 being enrolled in an ERA-NET NEURON-funded study (iBioStroke). We will apply automated analysis pipelines to obtain quantitative multi-dimensional measurements of edema severity. Our primary biomarker is the displacement of cerebrospinal fluid (ΔCSF) that serves as a surrogate for the volume of swelling that has developed after stroke. However, we will also measure hemispheric CSF ratio and lesional water uptake as additional edema phenotypes. We will model edema formation (in relation to time from stroke onset) to evaluate the degree to which biologic factors, such as age, sex, glucose, blood pressure, and renal function, influence edema formation. Our central hypothesis is that inter-patient variability in edema formation can be linked to both targetable clinical factors such as hyperglycemia and informative genetic differences. Our preliminary data has suggested that ΔCSF has a significant heritable component. Specific Aim 1 seeks to quantify the relationship of key clinical factors, such as hyperglycemia and blood pressure, to edema formation. We will leverage genomic data to further dissect which factors are causative in edema formation, using Mendelian randomization. We will also quantify the impact of edema and hemorrhagic transformation on stroke recovery. Specific Aim 2 will identify genes and pathways associated with cerebral edema after stroke. It will employ genome-wide association (GWAS) approaches with multiple edema phenotypes in this large cohort. We will further prioritize genes and pathways using functional annotation tools. Specific Aim 3 will dissect shared versus edema-specific injury mechanisms by analyzing edema in relation to traits such as hemorrhagic transformation, white matter injury and small-vessel disease. It will leverage large existing datasets to boost the power of gene discovery from Aim 2. Once complete, this work will provide the first comprehensive picture of the genetic architecture of cerebral edema after stroke and provide unbiased, novel insights into molecular targets that can inform drug discovery.