Translational assessment of sulfonylurea receptor-1 as a biomarker and therapeutic target for cerebral edema in traumatic brain injury

项目摘要 在翻译关于脑水肿复杂潜在机制的临床前工作方面存在着根本的差距 创伤性脑损伤(TBI)到急需的生物标记物和靶向/预防性治疗以改善预后 人类。这是一个重要的问题，因为不加区别地治疗脑水肿的临床方法仍然是反应性的。 以及病态-使一个问题复杂化，而这个问题是导致脑外伤死亡和残疾的根本原因。长期的 研究的目标是更好地了解脑损伤中水肿通路的作用和相互作用。这将是重点 创新成功的靶向治疗。K23的总体目标是开发一种全面的方法 为了了解人类脑损伤中涉及跨膜蛋白的独特的关键脑水肿途径： 磺脲类药物受体-1(Sur1)。建立在生物学中心教条的基础上，这一建议评估了超大脑 通过研究人类Sur1基因的表达和遗传变异，从多个角度研究脑外伤与水肿的关系，以及 补充这一点的是一种临床上相关的、独特的、产生水肿的小鼠模型。中心假设是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。这个 假设是根据申请者产生的初步数据制定的，这些数据强烈表明了可行性。这个 这项提议的基本原理是，用相关动物补充人脑损伤中Sur1的表达和遗传学 这一模式具有直接转化为改善临床护理和结果的潜力。预计这将通知患者 风险分层、监测、预后和针对性/开发特定的治疗方法。目标1评估这一关系 在人类Sur1表达(通过酶联免疫吸附试验在脑脊液、脑脊液中检测到)、 脑水肿和脑外伤的转归。目的2评估人类Sur1基因(ABCC8)标签单核苷酸多态性 (SNP)与脑外伤后脑水肿的相关性。AIM 3生成Sur1表达的时空地图(通过验证 技术)，并量化了格列本脲在脑外伤小鼠模型中抑制Sur1的效果。这个 申请人认为，这种方法是创新的，因为它在分子上补充了普通颅内压(ICP) 通过关注关键途径来监测和应对脑水肿，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。这些目标有望确立《Sur1》作为一部小说的实用性 生物标志物，并评价其作为预防和治疗水肿病的靶点。拟议的工作意义重大，因为它 对监测和预防脑水肿具有潜在的开创性影响，可能会降低发病率和 死亡率，不仅是在脑外伤，而且在许多其他神经疾病。研究计划得到了专家指导的加强 和严格的说教训练。总之，这将为应聘者在翻译方面提供必要的职业发展 研究方法和生物标志物科学、现代遗传学和统计学。这些协同工具培育了 过渡到独立所需的技能。它为R01-评估Sur1之间的相互作用的项目奠定了基础 临床试验中的表达、遗传学和抑制。这项工作将把调查员定位为未来的领导者 针对脑水肿的个体化靶点的开发以改善脑外伤的预后。

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.