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
基本信息
- 批准号:10396240
- 负责人:
- 金额:$ 12.52万
- 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:2017-06-15 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
PROJECT ABSTRACT
There is a fundamental gap in translating preclinical work on complex underlying mechanisms of cerebral edema in
traumatic brain injury (TBI) to critically needed biomarkers and targeted/preventive therapies for improving outcomes in
humans. This is an important problem because indiscriminate clinical approaches to cerebral edema remain reactionary
and morbid - compounding a problem that is a fundamental contributor to death and disability in TBI. The long-term
research goal is to better understand the roles and interactions of edema pathways in human TBI. This will focus
innovation of successful targeted treatments. The overall objective of this K23 is to develop a comprehensive approach
towards understanding a unique, key pathway of cerebral edema in human TBI involving a transmembrane protein:
Sulfonylurea Receptor-1 (Sur1). Founded on the central dogma of biology, this proposal evaluates the Sur1-cerebral
edema relationship in TBI from multiple angles by investigating Sur1 expression and genetic variability in humans, and
complementing this with a clinically relevant, unique, edema-generating mouse-model. The central hypotheses are that 1)
Sur1 levels and genetic variability influence cerebral edema and 2) Sur1 expression patterns guide treatment efficacy. The
hypotheses have been formulated upon preliminary data generated by the applicant that strongly suggest feasibility. The
rationale for the proposal is that complementing Sur1 expression and genetics in human TBI with a relevant animal
model, has the potential to directly translate to improving clinical care and outcomes. This is expected to inform patient
risk stratification, monitoring, prognosis, and targeting/developing specific therapies. Aim 1 evaluates the relationship
between human Sur1 expression (detected in cerebrospinal fluid, CSF, by enzyme linked immunosorbent assay, ELISA),
cerebral edema, and TBI outcomes. Aim 2 evaluates the human Sur1 gene (ABCC8) tag-single nucleotide polymorphism
(SNP) associations with cerebral edema in TBI. Aim 3 generates a temporo-spatial map of Sur1 expression (by validated
techniques) and quantifies effects of Sur1 inhibition by glyburide in an edema-generating mouse-model of TBI. The
approach is innovative, in the applicant's opinion, because it molecularly complements generic intracranial pressure (ICP)
monitoring and responses to cerebral edema by focusing on a key pathway, and uses a multifaceted approach to bridge the
gap between animal models and human disease. These aims are expected to establish the utility of Sur1 as a novel
biomarker and evaluate it as a preventive therapeutic target against edema. The proposed work is significant because it
has potential groundbreaking implications for monitoring and preventing cerebral edema that may reduce morbidity and
mortality, not just in TBI, but in many other neurological disorders. The research plan is augmented by expert mentoring
and rigorous didactic training. Together, this will provide the candidate with essential career development in translational
research methodologies and the science of biomarkers, modern genetics, and statistics. These synergistic tools cultivate
skills necessary for transition to independence. It sets the stage for R01-projects evaluating the interplay between Sur1
expression, genetics and inhibition in clinical trials. This work will uniquely position the investigator as a future leader in
the development of individualized targets against cerebral edema to improve outcomes in TBI.
项目摘要
在将关于脑水肿复杂的潜在机制的临床前工作转化为临床研究方面存在根本性的差距,
创伤性脑损伤(TBI),以改善预后的急需的生物标志物和靶向/预防性治疗,
人类这是一个重要的问题,因为不加区别的临床方法脑水肿仍然反动
和病态-加重了一个问题,这是一个基本的贡献者死亡和残疾的创伤性脑损伤。长期
研究目标是更好地理解水肿途径在人类TBI中的作用和相互作用。购买将侧重
成功的靶向治疗的创新。K23的总体目标是制定一种全面的方法,
为了了解一个独特的,关键的途径脑水肿在人类创伤性脑损伤涉及一个跨膜蛋白:
磺酰脲受体-1(Sur1)。建立在生物学中心法则的基础上,这项建议评估了Sur1-大脑
通过研究Sur1在人类中的表达和遗传变异性,从多个角度研究TBI与水肿的关系,
用临床相关的、独特的、产生水肿的小鼠模型补充这一点。核心假设是:(1)
Sur1水平和遗传变异性影响脑水肿和2)Sur1表达模式指导治疗效果。的
根据申请人提供的初步数据提出了一些假设,这些数据有力地表明了可行性。的
该提议的基本原理是用相关动物补充人TBI中的Sur1表达和遗传学,
模型,有可能直接转化为改善临床护理和结果。预计这将告知患者
风险分层、监测、预后和靶向/开发特定疗法。目标1评估关系
人Sur1表达(通过酶联免疫吸附测定,ELISA在脑脊液,CSF中检测),
脑水肿和TBI结果。目的2检测人类Sur1基因(ABCC8)标签单核苷酸多态性
(SNP)与TBI中脑水肿的相关性。目的3生成Sur1表达的时空图(通过验证
技术),并量化了在TBI的产生水肿的小鼠模型中格列本脲对Sur1抑制的作用。的
申请人认为,这种方法是创新的,因为它在分子上补充了一般颅内压(ICP)
监测和应对脑水肿的重点是一个关键的途径,并使用多方面的方法来弥合
动物模型和人类疾病之间的差距。这些目标预计将建立效用的苏尔1作为一种新的
生物标志物,并将其作为水肿的预防性治疗靶点进行评估。这项工作意义重大,因为它
对于监测和预防脑水肿具有潜在的开创性意义,可以降低发病率,
死亡率,不仅仅是TBI,还有许多其他神经系统疾病。研究计划由专家指导
严格的教学训练。总之,这将为候选人提供翻译方面的基本职业发展
研究方法和生物标志物科学,现代遗传学和统计学。这些协同工具培养
向独立过渡所需的技能。它为R01项目评估Sur1之间的相互作用奠定了基础
临床试验中的表达、遗传学和抑制。这项工作将使研究者成为未来的领导者,
开发针对脑水肿的个体化靶点,以改善TBI的结局。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ruchira Menka Jha其他文献
Ruchira Menka Jha的其他文献
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{{ 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:
$ 12.52万 - 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:
$ 12.52万 - 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:
10612416 - 财政年份:2021
- 资助金额:
$ 12.52万 - 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:
$ 12.52万 - 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:
$ 12.52万 - 项目类别:
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