A Translational Evaluation of Sur1-Trpm4 Imaging Endophenotypes and Genetics to Direct Precision Medicine for Cerebral Edema After Traumatic Brain Injury

Sur1-Trpm4 成像内表型和遗传学的转化评估指导精准医学治疗脑外伤后脑水肿

基本信息

项目摘要

For decades, there has been a critical gap in translating preclinical work on mechanisms of cerebral edema in traumatic brain injury (TBI) to clinically available targeted therapies that improve outcome. This is important because cerebral edema management commands substantial clinical and financial resources in severe TBI, yet it remains a common cause of death and disability. Current treatments are indiscriminate, reactionary and morbid - none improve outcome. Guideline-based protocols use a templated approach to this immensely complex process without addressing individual differences in contributory pathways or edema endophenotypes. The long -term goal is to harness relevant individual data (genetic, molecular, imaging, physiologic) to direct a precision medicine approach to treat TBI edema and related contusion expansion. This R01 focuses on logical next steps to address existing knowledge gaps in a unique, key edema pathway involving Sulfonylurea receptor-1 (Sur1) and its regulated cation channel Trpm4. Promising results from Sur-1 inhibition (Glyburide, GLY) in preclinical and early clinical brain injury trials have generated exciting momentum in this pathway. The objective of this translational R01 is to define the impact of Sur1-Trpm4 related genetic and protein variability on different edema endophenotypes, contusion growth and response to inhibition in preclinical and human TBI. The rationale is that identifying these individual differences directly informs patient risk-stratification, prognosis, trial design, and targeted therapy; ultimately improving outcome. The central hypothesis is that Sur1 protein expression and genetic variability influence the endophenotype, extent, and therapeutic response of TBI edema. Aim 1 defines correlations between Sur1-Trpm4 expression and MRI edema endophenotypes in three clinically relevant complementary mouse models. Aim 2 tests effects of Sur1 inhibition (GLY, inducible knockout) in these models on MRI edema endophenotypes, contusion, and outcome. Aim 3 identifies impact of genetic variation in the Sur1 pathway on TBI edema and contusion growth (on imaging) in a single-center human test-cohort, and a multicenter validation-cohort. The work is feasible as shown by robust preliminary results and the tools, expertise and track record of successful collaborations among coinvestigators. This work is innovative in concept and methodology: it shifts a guideline-based paradigm toward precision medicine, links clinically measurable edema endophenotypes (MRI) with a molecular pathway and targeted inhibition in different TBI models, and uses a novel transgenic mouse to generate Sur1-Trpm4 expression maps. This research is significant, with high impact if successful: linking Sur1-Trpm4 expression and inhibition to MRI endophenotypes (Aims 1-2) directly translate to identifying appropriate patients for targeted therapy and trials. Distinguishing high vs low risk genetic profiles (Aim-3) will identify patients in whom Sur1-Trpm4 is a major contributor to TBI edema and contusion growth, and channel inhibition may be highly beneficial- directing clinical care and trials. Ultimately, such knowledge has the potential to transform precision-medicine care of this devastating secondary injury and improve TBI outcome.
几十年来,在将关于脑水肿机制的临床前工作转化为脑水肿的临床前工作方面, 创伤性脑损伤(TBI)的临床可用的靶向治疗,改善结果。这很重要 因为脑水肿的治疗需要大量的临床和财政资源, 它仍然是造成死亡和残疾的常见原因。目前的治疗是不分青红皂白的,反动的和病态的 - 没有改善结果。基于指南的协议使用模板化的方法来处理这个极其复杂的 在没有解决贡献途径或水肿内表型的个体差异的情况下,长 - 长期目标是利用相关的个体数据(遗传,分子,成像,生理)来指导精确的 治疗TBI水肿和相关挫伤扩大的药物方法。此R 01侧重于逻辑后续步骤 解决涉及磺酰脲受体-1(Sur 1)的独特关键水肿途径中的现有知识缺口 及其调节的阳离子通道Trpm 4。Sur-1抑制(格列本脲,GLY)在临床前的有希望的结果 早期临床脑损伤试验已经在这一途径中产生了令人兴奋的动力。的目的 翻译R 01是为了定义Sur 1-Trpm 4相关的遗传和蛋白变异性对不同水肿的影响, 内表型、挫伤生长和对临床前和人TBI抑制的反应。基本原理是 识别这些个体差异直接告知患者风险分层、预后、试验设计, 靶向治疗;最终改善结果。中心假设是Sur 1蛋白表达和 遗传变异性影响TBI水肿的内表型、程度和治疗反应。目标1定义 Sur 1-Trpm 4表达与MRI水肿内表型之间的相关性 互补的小鼠模型。目的2在这些模型中测试Sur 1抑制(GLY,诱导型敲除)的效果 MRI水肿内表型、挫伤和结局。目的3确定Sur 1中遗传变异的影响 在单中心人类测试队列中TBI水肿和挫伤生长(成像)的途径,以及 多中心验证队列。这项工作是可行的,因为强大的初步结果和工具,专业知识 以及共同研究者之间成功合作的记录。这项工作在概念上是创新的, 方法学:它将基于指南的范式转变为精确医学,将临床可测量的水肿 内表型(MRI)与分子途径和靶向抑制在不同的TBI模型,并使用 新的转基因小鼠产生Sur 1-Trpm 4表达图谱。这项研究意义重大,影响巨大 如果成功:将Sur 1-Trpm 4表达和抑制与MRI内表型联系起来(目的1-2) 为靶向治疗和试验寻找合适的患者。区分高风险与低风险遗传特征 (目标-3)将确定Sur 1-Trpm 4是TBI水肿和挫伤生长的主要原因的患者,以及 通道抑制可能是非常有益的-指导临床护理和试验。最终,这些知识 有可能改变这种毁灭性的继发性损伤的精确医学护理,并改善TBI的结果。

项目成果

期刊论文数量(14)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Fluid therapy after brain injury: the pendulum swings again.
  • DOI:
    10.1016/s1474-4422(21)00204-0
  • 发表时间:
    2021-08
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kochanek PM;Jha RM
  • 通讯作者:
    Jha RM
Precision Effects of Glibenclamide on MRI Endophenotypes in Clinically Relevant Murine Traumatic Brain Injury.
  • DOI:
    10.1097/ccm.0000000000005749
  • 发表时间:
    2023-02-01
  • 期刊:
  • 影响因子:
    8.8
  • 作者:
  • 通讯作者:
Cerebrospinal Fluid Sulfonylurea Receptor-1 is Associated with Intracranial Pressure and Outcome after Pediatric TBI: An Exploratory Analysis of the Cool Kids Trial.
脑脊液磺酰脲受体 1 与颅内压和儿科 TBI 后的结果相关:Cool Kids 试验的探索性分析。
  • DOI:
    10.1089/neu.2020.7501
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    4.2
  • 作者:
    Zusman,BenjaminE;Kochanek,PatrickM;Bell,MichaelJ;Adelson,PDavid;Wisniewski,StephenR;Au,AliciaK;Clark,RobertSB;Bayır,Hülya;Janesko-Feldman,Keri;Jha,RuchiraM
  • 通讯作者:
    Jha,RuchiraM
Multifaceted Benefit of Whole Blood Versus Lactated Ringer's Resuscitation After Traumatic Brain Injury and Hemorrhagic Shock in Mice.
  • DOI:
    10.1007/s12028-020-01084-1
  • 发表时间:
    2021-06
  • 期刊:
  • 影响因子:
    3.5
  • 作者:
    Zusman BE;Kochanek PM;Bailey ZS;Leung LY;Vagni VA;Okonkwo DO;Puccio AM;Shutter LA;Janesko-Feldman KL;Gilsdorf JS;Shear DA;Jha RM
  • 通讯作者:
    Jha RM
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Ruchira Menka Jha其他文献

Ruchira Menka Jha的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Ruchira Menka Jha', 18)}}的其他基金

A Single Cell and Proteomic Precision Medicine Approach to Glyburide Responsive Contusion Expansion in Severe Traumatic Brain Injury
单细胞和蛋白质组精准医学方法治疗严重创伤性脑损伤中的格列本脲反应性挫伤扩张
  • 批准号:
    10645458
  • 财政年份:
    2023
  • 资助金额:
    $ 55.77万
  • 项目类别:
A Translational Evaluation of Sur1-Trpm4 Imaging Endophenotypes and Genetics to Direct Precision Medicine for Cerebral Edema After Traumatic Brain Injury
Sur1-Trpm4 成像内表型和遗传学的转化评估指导精准医学治疗脑外伤后脑水肿
  • 批准号:
    10401300
  • 财政年份:
    2021
  • 资助金额:
    $ 55.77万
  • 项目类别:
A Translational Evaluation of Sur1-Trpm4 Imaging Endophenotypes and Genetics to Direct Precision Medicine for Cerebral Edema After Traumatic Brain Injury
Sur1-Trpm4 成像内表型和遗传学的转化评估指导精准医学治疗脑外伤后脑水肿
  • 批准号:
    10117587
  • 财政年份:
    2021
  • 资助金额:
    $ 55.77万
  • 项目类别:
Translational assessment of sulfonylurea receptor-1 as a biomarker and therapeutic target for cerebral edema in traumatic brain injury
磺酰脲类受体1作为创伤性脑损伤脑水肿生物标志物和治疗靶点的转化评估
  • 批准号:
    10396240
  • 财政年份:
    2017
  • 资助金额:
    $ 55.77万
  • 项目类别:
Translational assessment of sulfonylurea receptor-1 as a biomarker and therapeutic target for cerebral edema in traumatic brain injury
磺酰脲类受体1作为创伤性脑损伤脑水肿生物标志物和治疗靶点的转化评估
  • 批准号:
    10183343
  • 财政年份:
    2017
  • 资助金额:
    $ 55.77万
  • 项目类别:

相似海外基金

Understanding how psychedelic drugs affect brain and behaviour in rodents
了解迷幻药物如何影响啮齿类动物的大脑和行为
  • 批准号:
    2897454
  • 财政年份:
    2023
  • 资助金额:
    $ 55.77万
  • 项目类别:
    Studentship
Does Vision Loss Affect Tauopathy in the Brain
视力丧失是否会影响大脑中的 Tau 蛋白病
  • 批准号:
    10670631
  • 财政年份:
    2023
  • 资助金额:
    $ 55.77万
  • 项目类别:
Neuroplasticity in songbirds: how changing behaviour and experience affect learning and the brain
鸣禽的神经可塑性:行为和经验的变化如何影响学习和大脑
  • 批准号:
    RGPIN-2018-04060
  • 财政年份:
    2022
  • 资助金额:
    $ 55.77万
  • 项目类别:
    Discovery Grants Program - Individual
Understanding brain maturation: How spontaneous cortical high frequency oscillations develop and affect executive function during childhood
了解大脑成熟:自发皮质高频振荡如何发展并影响儿童时期的执行功能
  • 批准号:
    RGPIN-2021-02948
  • 财政年份:
    2022
  • 资助金额:
    $ 55.77万
  • 项目类别:
    Discovery Grants Program - Individual
Peering into the future of neuroscience: how visual cues are processed in the avian brain to affect locomotion
展望神经科学的未来:鸟类大脑如何处理视觉线索以影响运动
  • 批准号:
    559062-2021
  • 财政年份:
    2022
  • 资助金额:
    $ 55.77万
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Doctoral
How does environmental enrichment affect brain development?
丰富的环境如何影响大脑发育?
  • 批准号:
    DP210102473
  • 财政年份:
    2021
  • 资助金额:
    $ 55.77万
  • 项目类别:
    Discovery Projects
Peering into the future of neuroscience: how visual cues are processed in the avian brain to affect locomotion
展望神经科学的未来:鸟类大脑如何处理视觉线索以影响运动
  • 批准号:
    559062-2021
  • 财政年份:
    2021
  • 资助金额:
    $ 55.77万
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Neuroplasticity in songbirds: how changing behaviour and experience affect learning and the brain
鸣禽的神经可塑性:行为和经验的变化如何影响学习和大脑
  • 批准号:
    RGPIN-2018-04060
  • 财政年份:
    2021
  • 资助金额:
    $ 55.77万
  • 项目类别:
    Discovery Grants Program - Individual
Understanding brain maturation: How spontaneous cortical high frequency oscillations develop and affect executive function during childhood
了解大脑成熟:自发皮质高频振荡如何发展并影响儿童时期的执行功能
  • 批准号:
    RGPIN-2021-02948
  • 财政年份:
    2021
  • 资助金额:
    $ 55.77万
  • 项目类别:
    Discovery Grants Program - Individual
Does menthol affect nicotine's impact on brain reinforcement mechanisms in dependent and nondependent users of electronic nicotine delivery systems?
薄荷醇是否会影响尼古丁对电子尼古丁输送系统的依赖和非依赖用户的大脑强化机制的影响?
  • 批准号:
    445102
  • 财政年份:
    2021
  • 资助金额:
    $ 55.77万
  • 项目类别:
    Operating Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了