GENETICS AND PREDICTION OF CEREBRAL EDEMA AFTER HEMISPHERIC STROKE

半球卒中后脑水肿的遗传学和预测

基本信息

  • 批准号:
    10020442
  • 负责人:
  • 金额:
    $ 17.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 脑卒中后第一周神经功能恶化的最大原因是大脑的发育 梗塞区域周围肿胀。然而,只有一半的大中风患者会发展为恶性 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水肿的程度。相反,很可能内在的 中风后激活的细胞机制和生物途径的差异有助于观察到的 膨胀的不均匀性。我们相信,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,可能导致改善水肿的靶向治疗 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志物, 测量中风肿胀时从大脑中排出的脑脊液量。这项措施(CSCSF)已被 在初步研究中得到了验证,我们现在将通过在任何时间点(无论何时)对CRFCSF进行建模来完善它。 使用已经采集的400次扫描结合我们开发的自动算法进行CT)。 这种中间表型将捕获水肿形成的速率,并能够量化哪些患者 与那些相对受到保护的人相比,具有相对恶性的轨迹(考虑到他们的中风严重程度, 梗塞面积)对抗水肿的发展。 我们正在继续从一项大型多中心急性卒中研究中招募的受试者中获取CT扫描, 我已经对近3,000名患者进行了基因分型(由我的主要导师Jin-Moo Lee的R 01基金支持 研究中风后的神经学改善)。我们将在这个更大的(仍然是) 扩展)队列并量化剩余变异性(调整临床协变量), 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是一种估计总遗传力的方法,随后进行全基因组关联研究,以确定 与我们持续测量水肿相关的常见多态性。这个公正的发现 这种方法将得到现代不断发展的手段的补充,这些手段可以发现罕见的变异和遗传变异。 这些途径可以进一步解释水肿的遗传性,并提供精确的生物学靶点。我也会 学习评估任何潜在的遗传标记与这些分析确定的功能意义。 我将在这些生物信息学和定量基因组方法的指导博士卡洛斯Cruchaga,一个 在使用定量内表型(例如CSF)剖析复杂性状方面具有特殊专长的遗传学家 tau水平作为阿尔茨海默病的中间表型)。 该项目不仅是对脑水肿遗传基础的首次研究, 一个研究途径,将继续为我走向独立的资金,以进一步了解水肿, 一种对所有形式的脑损伤都有重大意义的疾病。我计划继续建立在我的 通过复制和排序有前途的目标并通过研究扩展它们来进行培训和数据 汇聚表型,如中风后出血性转化。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, 恶性水肿的标志物最终,从水肿生物学中获得的信息可以告诉我们, 治疗干预,以阻止水肿,因为我们朝着精确的医学方法来管理 脑损伤

项目成果

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Rajat Dhar其他文献

Rajat Dhar的其他文献

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{{ truncateString('Rajat Dhar', 18)}}的其他基金

Genetic Architecture of Cerebral Edema after Stroke
中风后脑水肿的遗传结构
  • 批准号:
    10666702
  • 财政年份:
    2022
  • 资助金额:
    $ 17.91万
  • 项目类别:
Genetic Architecture of Cerebral Edema after Stroke
中风后脑水肿的遗传结构
  • 批准号:
    10446825
  • 财政年份:
    2022
  • 资助金额:
    $ 17.91万
  • 项目类别:
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
  • 财政年份:
    2017
  • 资助金额:
    $ 17.91万
  • 项目类别:
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:
    10237306
  • 财政年份:
    2017
  • 资助金额:
    $ 17.91万
  • 项目类别:
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
  • 财政年份:
    2017
  • 资助金额:
    $ 17.91万
  • 项目类别:
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