GENETICS AND PREDICTION OF CEREBRAL EDEMA AFTER HEMISPHERIC STROKE

半球卒中后脑水肿的遗传学和预测

• 批准号: 9754265
• 负责人: Rajat Dhar
• 金额: $ 17.91万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754265
• 关键词: Accounting; Algorithms; Alzheimer' s Disease; Area; Attenuated; Bioinformatics; Biological; Biology; Blood - brain barrier anatomy; Brain; Brain Edema; Brain Injuries; Cell Death; Cerebral Edema; Cessation of life; Clinical; Complex; Complication; Coupled; Data; Data Set; Deterioration; Development; Disease; Drug Targeting; Edema; Enrollment; Expressed Sequence Tags; Foundations; Funding; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Risk; Genetic Variation; Genetic study; Genomic approach; Genomics; Genotype; Goals; Grant; Hemorrhage; Heritability; Heterogeneity; Image; Infarction; Inflammation; Intervention; Knowledge; Lead; Learning; Malignant - descriptor; Measurement; Measures; Medical Genetics; Mentors; Methods; Modeling; Modernization; Molecular; Nature; Neurologic; Operative Surgical Procedures; Outcome; Pathway Analysis; Pathway interactions; Patients; Phenotype; Process; Research; Residual state; Risk; Scanning; Severities; Site; Stroke; Structure; Subgroup; Swelling; Techniques; Testing; Therapeutic Intervention; Time; Training; Traumatic Brain Injury; Variant; Work; X-Ray Computed Tomography; acute stroke; cohort; endophenotype; follow-up; genetic architecture; genetic makeup; genetic variant; genome wide association study; genome-wide; genotyped patients; high risk; imaging genetics; improved; individual response; innovation; novel marker; post stroke; precision medicine; quantitative imaging; rare variant; stroke patient; success; tau Proteins; trait; tumor

PROJECT SUMMARY The greatest contributor to neurological deterioration in the first week after stroke is development of brain swelling around the area of infarction. However, only half of those with large strokes develop malignant cerebral edema sufficient to compress adjacent brain structures and threaten survival. Clinical factors including stroke size do not explain the degree of edema that develops. Instead, it is likely that intrinsic differences in cellular mechanisms and biologic pathways activated after stroke contribute to the observed heterogeneity in swelling. We believe that identifying the genetic factors underlying this biologic variability will provide important actionable knowledge that could lead to improved targeted treatments for edema and better prediction of who is at risk. In order to study the biology of cerebral edema, we need to capture the full spectrum of its severity with an accurate and quantifiable measure of swelling. We have developed a novel marker of edema severity that measures amount of CSF pushed out of the brain as the stroke swells. This measure (∆CSF) has been validated in a preliminary study and we will now refine it by modeling ∆CSF at any time point (whenever CT is performed, using 400 scans already acquired coupled to an automated algorithm we have developed). This intermediate phenotype will capture rate of edema formation and be able to quantify which patients have relatively malignant trajectories vs. those who are relatively protected (given their stroke severity and infarct size) against developing edema. We are continuing to acquire CT scans from subjects enrolled in a large multi-site acute stroke study that already has almost 3,000 patients genotyped (supported by my primary mentor, Jin-Moo Lee’s R01 grant studying neurological improvement after stroke). We will measure rate of ∆CSF in this larger (and still expanding) cohort and quantify the residual variability (adjusting for clinical covariates) in order to ascertain for potential genetic component. Our genomic analyses of this edema endophenotype will include GCTA, a means of estimating total heritability, followed by genome-wide association study to identify common polymorphisms associated with our continuous measure of edema. This unbiased discovery approach will be supplemented by modern evolving means of uncovering rare variants and genetic pathways that could further explain heritability of edema and provide refined biologic targets. I will also learn to evaluate the functional significance of any potential genetic markers identified with these analyses. I will be mentored in these bioinformatics and quantitative genomic methods by Dr. Carlos Cruchaga, a geneticist with special expertise in dissecting complex traits using quantitative endophenotypes (e.g. CSF tau levels as intermediate phenotypes for Alzheimer’s disease). This project represents not only the first study of the genetic basis of cerebral edema but also a first step in a research pathway that will continue as I move toward independent funding to further understand edema, a disease with immense significance across all forms of brain injury. I plan to continue building upon my training and data by replicating and sequencing promising targets and expanding upon them by studying convergent phenotypes such as hemorrhagic transformation after stroke. I will also leverage my training to construct a clinical-genetic risk score for edema after stroke, incorporating the most informative genetic markers for malignant edema. Ultimately, the information gained on biology of edema could inform therapeutic interventions to block edema as we move towards a precision-medicine approach to managing brain injury.

项目总结 导致中风后第一周神经恶化的最大因素是大脑的发育 梗死区周围肿胀。然而，在中风较大的患者中，只有一半会发展为恶性肿瘤。 脑水肿足以压迫邻近的脑结构并威胁生存。临床因素 包括中风的大小并不能解释形成的水肿的程度。相反，它很可能是内在的 卒中后激活的细胞机制和生物通路的差异导致观察到的 肿胀的不均一性。我们认为确定这种生物变异性背后的遗传因素 将提供重要的可操作的知识，可能导致改善针对浮肿的靶向治疗 以及更好地预测谁处于危险之中。 为了研究脑水肿的生物学，我们需要用一种 准确和可量化的肿胀测量。我们已经开发出一种新的水肿严重程度的标记物 测量中风时从大脑排出的脑脊液的量。这项措施(∆脑脊液)已被 在初步研究中经过验证，我们现在将通过在任何时间点(无论何时)对∆脑脊液进行建模来对其进行优化 使用已经采集的400次扫描以及我们开发的自动算法进行CT检查)。 这一中间表型将捕捉到水肿形成的比率，并能够量化哪些患者 有相对恶性的轨迹与那些相对受保护的人(考虑到他们的中风严重性和 梗死灶面积)，防止形成水肿。 我们正在继续获取参加大型多部位急性中风研究的受试者的CT扫描 已经有近3000名患者进行了基因分型(得到了我的主要导师李振武的R01赠款的支持 研究中风后的神经改善)。我们将测量∆脑脊液在这个更大的(仍然是 扩展)队列和量化残差(根据临床协变量进行调整)，以便 确定潜在的遗传成分。我们对这种水肿内表型的基因组分析将包括 GCTA，一种估计总遗传力的手段，随后进行全基因组关联研究，以确定 常见的多态现象与我们对水肿量的持续测量有关。这个不偏不倚的发现 方法将得到现代进化手段的补充，以发现罕见的变异和基因 这些途径可以进一步解释浮肿的遗传性，并提供精确的生物靶点。我也会 学会评估通过这些分析确定的任何潜在遗传标记的功能意义。 我将由卡洛斯·克鲁查加博士指导这些生物信息学和定量基因组学方法，他是一位 具有使用数量内表型(如脑脊液)解剖复杂性状的专门知识的遗传学家 Tau水平作为阿尔茨海默病的中间表型)。 这一项目不仅代表了对脑水肿遗传基础的第一次研究，也是在 随着我走向独立基金，以进一步了解水肿，这条研究道路将继续下去， 一种在所有形式的脑损伤中都具有巨大意义的疾病。我计划在我的基础上继续发展 通过复制和排序有希望的目标并通过研究对其进行扩展来训练和数据 卒中后出血性转化等趋同表型。我还将利用我的培训 构建卒中后水肿的临床-遗传风险评分，纳入最具信息量的基因 恶性水肿的标志物。最终，从生物学上获得的关于浮肿的信息可能会 在我们迈向精确医学管理方法的过程中，通过治疗干预来阻止浮肿 脑部受伤。