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 将脑水肿复杂的潜在机制的临床前工作转化为 创伤性脑损伤 (TBI) 急需的生物标志物和靶向/预防性治疗，以改善结果 人类。这是一个重要的问题，因为不加区别的临床治疗脑水肿的方法仍然是反动的 和病态 - 加剧了 TBI 死亡和残疾的根本原因。长期来看 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 成功的靶向治疗的创新。 K23 的总体目标是开发一种综合方法 旨在了解涉及跨膜蛋白的人类 TBI 脑水肿的独特关键途径： 磺酰脲受体-1 (Sur1)。该提案以生物学的中心法则为基础，评估了 Sur1-cerebral 通过研究人类 Sur1 表达和遗传变异性，从多个角度研究 TBI 中的水肿关系，以及 通过临床相关的、独特的、产生水肿的小鼠模型来补充这一点。中心假设是 1) Sur1 水平和遗传变异影响脑水肿，2) Sur1 表达模式指导治疗效果。这 根据申请人生成的初步数据提出了强烈建议可行性的假设。这 该提案的基本原理是用相关动物来补充人类 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。预计这将告知患者 风险分层、监测、预后以及针对/开发特定疗法。目标 1 评估关系 人类 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 结局。目标 2 评估人类 Sur1 基因 (ABCC8) 标签单核苷酸多态性 (SNP) 与 TBI 中脑水肿的关联。目标 3 生成 Sur1 表达的时空图（通过验证） 技术）并量化了格列本脲在产生水肿的 TBI 小鼠模型中抑制 Sur1 的效果。这 申请人认为该方法是创新的，因为它在分子上补充了通用颅内压（ICP） 通过关注关键途径来监测和应对脑水肿，并采用多方面的方法来弥合 动物模型与人类疾病之间的差距。这些目标预计将确立 Sur1 作为小说的效用 生物标志物并评估其作为水肿的预防性治疗靶点。拟议的工作意义重大，因为它 对于监测和预防脑水肿具有潜在的突破性意义，可以降低发病率和 死亡率，不仅是 TBI，还包括许多其他神经系统疾病。研究计划得到专家指导的补充 和严格的教学培训。总之，这将为候选人提供转化方面的重要职业发展 研究方法和生物标记科学、现代遗传学和统计学。这些协同工具培养 过渡到独立所需的技能。它为评估 Sur1 之间相互作用的 R01 项目奠定了基础 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领导者的独特地位 开发针对脑水肿的个体化目标以改善 TBI 的结果。

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