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

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（Sur 1）。建立在生物学中心法则的基础上，这项建议评估了Sur 1-大脑 通过研究Sur 1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） Sur 1水平和遗传变异性影响脑水肿和2）Sur 1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 该提案的基本原理是用相关动物补充人类TBI中的Sur 1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Sur 1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Sur 1基因（ABCC 8）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Sur 1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Sur 1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R 01项目评估Sur 1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。

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.