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系统恶化和院内死亡的主要剖腹产的主要因素中风后。大多数半肝中的脑部肿胀都没有升高中风恢复与梗塞的生长一样多。 thas knoledge差距阻碍了发展。有针对性的干预措施以减轻与脑创伤一样多样化的习惯，肿瘤，出血和缺血性中风。尽管中风和严重程度相似，但表现出恶性水肿和其他人，但没有轻度肿胀这是将成像与遗传学整合以识别关键生物制剂途径和介质与大脑水肿有关。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性。我们的主要生物标志物是脑脊液（ΔCSF）的位移中风后出现的肿胀也将测量CSF比率。和病变的水作为其他水肿表型。从中风开始），以评估生物学因素的程度肾功能，影响水肿的形成。形成可以与可靶向的临床因素（例如高血糖和信息遗传）有关差异 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哪些因素使用Mendelian随机化。中风恢复2 将在这个大型队列中与水肿表型一起使用劳动范围的联想（GWAS）。我们将使用功能注释工具进一步优先考虑基因和途径。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，白质损伤和血管疾病。 AIM 2从AIM 2发现基因的力量。一旦压缩，是第一张曲目图片中风后大脑水肿的遗传结构，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。