Genetic Architecture of Cerebral Edema after Stroke

中风后脑水肿的遗传结构

基本信息

批准号：
10666702
负责人：
Rajat Dhar
金额：
$ 47万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666702
关键词：
Acute Age Attenuated Biological Biological Factors Biological Markers Biology Blood Pressure Brain Edema Brain Injuries Brain hemorrhage Cerebral Edema Cerebrospinal Fluid Cerebrum Cessation of life Clinical Data Data Set Databases Deterioration Development Dimensions Disparate Edema Enrollment Exhibits Funding Genes Genetic Genetic study Genomics Genotype Glucose Goals Growth Hemorrhage Heritability Heterogeneity Hospitals Human Hyperglycemia Hypertension Image Impairment Infarction Injury Intervention Intracranial Pressure Ion Channel Ischemia Ischemic Stroke Knowledge Link Malignant - descriptor Measurement Measures Mediating Mediator Mendelian randomization Microvascular Dysfunction Modeling Molecular Molecular Target National Institute of Neurological Disorders and Stroke Neurologic Neurons Outcome Participant Pathologic Pathway interactions Patients Phenotype Population Quantitative Genetics Recovery Renal function Reperfusion Therapy Risk Sample Size Severities Source Stroke Swelling Time Tissues Trauma Traumatic Brain Injury Water Work X-Ray Computed Tomography acute stroke analysis pipeline annotation system automated analysis automated image analysis bioinformatics tool blood-brain barrier permeabilization brain tissue brain volume cohort density drug discovery effective therapy empowerment follow-up gene discovery genetic architecture genetic information genetic variant genome wide association study genomic data imaging genetics improved outcome injured insight interpatient variability novel patient variability post stroke prevent quantitative imaging repository response sex stroke outcome stroke patient stroke recovery success targeted treatment trait tumor uptake white matter injury

项目摘要

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.

项目摘要大脑水肿是神经定义的主要因素，是院内死亡的主要原因中风后。这种病理水的积累导致大脑体积的增加，可以测量经过大多数半球的中风。这种大脑肿胀不仅增加了大脑疝的风险，还会损害中风恢复与梗塞增长一样多。但是，关键的生物学因素和分子机制大脑水肿的介导形成仍然很差。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，如脑创伤等潜水员肿瘤，出血性和缺血性中风。患者之间存在显着差异，有些表现出恶性水肿和其他人，没有一个轻度肿胀的目的地类似的中风大小和严重性。这该建议的核心目的是将成像与遗传学整合，以识别关键的生物学途径和在大脑水肿中实施的介质。我们将从Ninds资助的3,506名患者中获取连续的CT扫描中风遗传学研究（GENISI）和1,000名由ERA-NET神经元资助的研究（IBIOSTROKE）纳入了1,000名。我们将应用自动分析管道以获得水肿的定量多维测量严重程度。我们的主要生物标志物是脑脊液（ΔCSF）的位移，它是替代的中风后发生的肿胀量。但是，我们还将测量半球CSF比率和病变的水吸收作为其他水肿表型。我们将建模水肿形成（与时间有关从中风开始），以评估年龄，性别，葡萄糖，血压等生物学因素的程度和肾功能，影响水肿形成。我们的中心假设是水肿间变异性形成可以与诸如高血糖和信息通用的临床因素有关差异。我们的初步数据表明ΔCSF具有重要的可遗传成分。具体目标 1试图量化关键临床因素（例如高血糖和血压）与水肿的关系形成。我们将利用基因组数据进一步剖析浮肿形成中哪些因素，使用孟德尔随机化。我们还将量化水肿和出血转化对中风恢复。特定的目标2将识别中风后与脑水肿相关的基因和途径。它将在这个大型队列中采用与多种水肿表型采用全基因组关联（GWAS）方法。我们将使用功能注释工具进一步优先考虑基因和途径。特定目标3将剖析共享通过分析与出血性特征有关的水肿与水肿特异性损伤机制转化，白质损伤和小血管疾病。它将利用大型现有数据集来提高 AIM 2从AIM 2发现基因的力量。一旦完成，这项工作将提供第一张全面的图片中风后脑水肿的遗传结构，并提供了对分子的无偏新见解可以告知药物发现的目标。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Automated Quantification of Compartmental Blood Volumes Enables Prediction of Delayed Cerebral Ischemia and Outcomes After Aneurysmal Subarachnoid Hemorrhage.

室室血容量的自动定量可以预测迟发性脑缺血和动脉瘤性蛛网膜下腔出血后的结果。

DOI：
10.1016/j.wneu.2022.10.105
发表时间：
2023
期刊：
World neurosurgery
影响因子：
2
作者：
Yuan,JaneY;Chen,Yasheng;Jayaraman,Keshav;Kumar,Atul;Zlepper,Zach;Allen,MichelleL;Athiraman,Umeshkumar;Osbun,Joshua;Zipfel,Gregory;Dhar,Rajat
通讯作者：
Dhar,Rajat

Collateral Status, Reperfusion, and Cerebral Edema After Thrombectomy for Stroke.

中风血栓切除术后的侧支状况、再灌注和脑水肿。