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
• 负责人: Ruchira Menka Jha
• 金额: $ 18.87万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183343
• 关键词: Acute; Address; Affect; American; Animal Model; Biological Markers; Biology; Brain; Brain Edema; Caring; Cations; Cause of Death; Cells; Cerebral Edema; Cerebrospinal Fluid; Cessation of life; Clinical; Clinical Trials; Code; Complement; Complex; Craniotomy; DNA; Data; Development; Development Plans; Diabetes Mellitus; Diffuse; Dose; Edema; Enzyme-Linked Immunosorbent Assay; FDA approved; Foundations; Funding; Future; Gene Frequency; Generations; Genes; Genetic; Genetic Variation; Genotype; Glasgow Outcome Scale; Glyburide; Goals; Heart Arrest; Hemorrhagic Shock; Hour; Human; Hypotension; Ideal 1; Immunofluorescence Immunologic; Infusion procedures; Integral Membrane Protein; Intracranial Pressure; Introns; Knowledge; Maps; Measures; Mediating; Mentors; Minor; Mission; Modeling; Modernization; Molecular; Monitor; Morbidity - disease rate; Multiple Trauma; Neurologic; Osmolar Concentration; Outcome; Pathway interactions; Patient Monitoring; Patient Selection; Patient risk; Patients; Pattern; Pharmaceutical Preparations; Positioning Attribute; Pre-Clinical Model; Prevention; Preventive; Preventive therapy; Prognosis; Property; Proteins; Public Health; Regulation; Research; Research Methodology; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sampling; Science; Scientist; Seminal; Single Nucleotide Polymorphism; Stroke; Structure; Techniques; Testing; Training; Translating; Translational Research; Translations; Traumatic Brain Injury; Treatment Efficacy; United States National Institutes of Health; Water; Work; X-Ray Computed Tomography; bench to bedside; care outcomes; career development; clinical care; clinical investigation; clinically relevant; controlled cortical impact; disability; functional outcomes; human disease; improved; improved outcome; individualized medicine; innovation; insight; mortality; mouse model; nervous system disorder; novel marker; outcome prediction; personalized strategies; potential biomarker; pre-clinical; precision medicine; prevent; prospective; response; risk stratification; skills; statistics; sulfonylurea receptor; targeted treatment; therapeutic target; tool; treatment response

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 在翻译有关脑水肿的复杂潜在机制上的临床前工作的基本差距 创伤性脑损伤（TBI）至急需的生物标志物和针对性/预防疗法，以改善预后 人类。这是一个重要的问题 和病态 - 复杂一个问题，这是TBI死亡和残疾的基本贡献者。长期 研究目标是更好地了解水肿途径在人类TBI中的作用和相互作用。这将集中精力 成功的目标治疗的创新。该K23的总体目标是开发一种全面的方法 要了解人类TBI中脑水肿的独特，关键途径，该途径涉及跨膜蛋白： 磺酰脲受体1（SUR1）。该提案建立在生物学的中央教条上，评估了SUR1-脑部 通过研究人类的SUR1表达和遗传变异性，TBI的水肿关系来自TBI，并且 与临床相关的，独特的，浮肿生成的小鼠模型相辅相成。中心假设是1） SUR1水平和遗传变异影响脑水肿和2）SUR1表达模式指导治疗功效。这 假设已根据申请人产生的初步数据提出，强烈建议可行性。这 该提议的理由是，与相关动物相互补充人类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。这预计将告知病人 风险分层，监测，预后和靶向/开发特定疗法。目标1评估关系 在人类SUR1表达之间（在脑脊液中检测到CSF，通过酶连接的免疫吸附测定，ELISA），）， 大脑水肿和TBI结果。 AIM 2评估人类SUR1基因（ABCC8）标签单核苷酸多态性 （SNP）与TBI中的脑水肿相关。 AIM 3生成SUR1表达式的颞空间图（通过验证 技术）并量化了通过Glyburide在TBI的水肿生成小鼠模型中抑制SUR1的作用。这 在申请人的看来，方法是创新的，因为它分子补充了通用颅内压（ICP） 通过专注于关键途径，监测和对脑水肿的反应，并使用多方面的方法桥接 动物模型与人类疾病之间的差距。这些目标有望确定SUR1的实用性作为新颖 生物标志物并将其视为防止水肿的预防性治疗靶标。拟议的工作很重要，因为它 对监测和预防脑水肿具有潜在的突破性含义，这可能会降低发病率和 死亡率，不仅在TBI中，而且在许多其他神经系统疾病中。专家指导增强了研究计划 和严格的教学训练。一起，这将为候选人提供转化的重要职业发展 研究方法与生物标志物，现代遗传学和统计学的科学。这些协同工具培养了 过渡到独立所需的技能。它为评估SUR1之间的相互作用的R01项目设定了阶段 在临床试验中的表达，遗传学和抑制作用。这项工作将独特地将调查员定位为未来的领导者 针对脑水肿的个性化靶标发展以改善TBI的预后。

项目成果

Toward a global and reproducible science for brain imaging in neurotrauma: the ENIGMA adult moderate/severe traumatic brain injury working group.

• DOI: 10.1007/s11682-020-00313-7
• 发表时间: 2021-04
• 期刊: Brain imaging and behavior
• 影响因子: 3.2
• 作者: Olsen A;Babikian T;Bigler ED;Caeyenberghs K;Conde V;Dams-O'Connor K;Dobryakova E;Genova H;Grafman J;Håberg AK;Heggland I;Hellstrøm T;Hodges CB;Irimia A;Jha RM;Johnson PK;Koliatsos VE;Levin H;Li LM;Lindsey HM;Livny A;Løvstad M;Medaglia J;Menon DK;Mondello S;Monti MM;Newcombe VFJ;Petroni A;Ponsford J;Sharp D;Spitz G;Westlye LT;Thompson PM;Dennis EL;Tate DF;Wilde EA;Hillary FG
• 通讯作者: Hillary FG

Arresting edema: Important after anoxic brain injury?

• DOI: 10.1016/j.resuscitation.2019.02.009
• 发表时间: 2019-02
• 期刊: Resuscitation
• 影响因子: 6.5
• 作者: R. Jha;J. Elmer

Intracranial Pressure Trajectories: A Novel Approach to Informing Severe Traumatic Brain Injury Phenotypes.

• DOI: 10.1097/ccm.0000000000003361
• 发表时间: 2018-11
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Jha RM;Elmer J;Zusman BE;Desai S;Puccio AM;Okonkwo DO;Park SY;Shutter LA;Wallisch JS;Conley YP;Kochanek PM
• 通讯作者: Kochanek PM

A Precision Medicine Approach to Cerebral Edema and Intracranial Hypertension after Severe Traumatic Brain Injury: Quo Vadis?

• DOI: 10.1007/s11910-018-0912-9
• 发表时间: 2018-11-07
• 期刊: Current neurology and neuroscience reports
• 影响因子: 5.6
• 作者: Jha RM;Kochanek PM
• 通讯作者: Kochanek PM

"Take a Number"-Precision Monitoring Directs Precision Therapy.

“取数”——精准监测指导精准治疗。

• DOI: 10.1007/s12028-020-00941-3
• 发表时间: 2020
• 期刊: Neurocritical care
• 影响因子: 3.5
• 作者: Kochanek,PatrickM;Jha,RuchiraM;Clark,RobertSB
• 通讯作者: Clark,RobertSB