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: 9386514
• 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/9386514
• 关键词: Accounting; Algorithms; Alzheimer' s Disease; Architecture; 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; Individual; 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; clinical imaging; cohort; endophenotype; follow-up; genetic makeup; genetic variant; genome wide association study; genome-wide; genotyped patients; high risk; imaging genetics; improved; innovation; novel marker; precision medicine; quantitative imaging; rare variant; response; 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.

项目摘要 中风后的第一周，神经学定义的最大贡献是大脑的发展 在梗塞区域肿胀。但是，只有一半的中风出现恶性肿瘤 脑水肿足以压缩相邻的大脑结构并威胁生存。临床因素 包括中风大小不能解释发展的水肿程度。相反，可能是固有的 中风后激活的细胞机制和生物途径的差异有助于观察到 肿胀的异质性。我们认为，确定这种生物学变异性的遗传因素 将提供重要的可操作知识，从而可以改善水肿的靶向疗法 更好地预测谁处于危险之中。 为了研究脑水肿的生物学，我们需要通过 准确，可量化的肿胀测量。我们已经开发了一种新颖的水肿严重性标记 随着中风膨胀，CSF的量度从大脑中推出。此度量（∆CSF）已经 在初步研究中验证，我们现在将通过在任何时间点对∆CSF进行建模（无论何时 使用已获得的400次扫描与我们开发的自动化算法相结合）。 这种中间表型将捕获浮肿形成率，并能够量化哪些患者 具有相对恶性的轨迹与那些受到相对保护的轨迹（鉴于他们的中风严重程度和 梗塞大小）反对发展水肿。 我们将继续从参加大型多站点急性中风研究的受试者中获取CT扫描，该研究 已经有近3,000名患者进行了基因分型（在我的主要心理支持下，Jin-Moo Lee的R01 Grant支持 研究中风后的神经系统改善。我们将在此较大的（仍在 扩展）队列并量化残余变异性（调整临床协变量），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，然后进行全基因组关联研究以识别 与我们连续测量水肿相关的常见多态性。这个无偏见的发现 现代发展的手段将补充方法的方法 可以进一步解释水肿的途径并提供了精致的生物学靶标。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。 我将在这些生物信息学和Carlos Cruchaga博士的定量基因组方法中进行修复 具有特殊专业知识的普通师使用定量内表型解剖复杂性状（例如CSF） tau水平为阿尔茨海默氏病的中间表型）。 该项目不仅代表了大脑水肿遗传基础的首次研究，而且还代表了 我将继续迈向独立资金以进一步了解水肿的研究途径， 在所有形式的脑损伤中具有巨大意义的疾病。我计划继续在我的 培训和数据通过复制和测序承诺目标，并通过研究对目标进行扩展 融合表型，例如中风后出血转化。我还将利用我的培训 构建中风后水肿的临床遗传风险评分，并结合最有用的通用性 恶性水肿的标记。最终，获得的有关水肿生物学的信息可以告知 当我们朝着管理中的精确医学方法时，治疗性干预措施可以阻止水肿 脑损伤。