Center of Biomedical Research Excellence in Acute Care Research and Rural Disparities

项目摘要 心脏骤停的发生率和死亡率都很高，只有不到7%的患者达到了 很好的神经学结果。表现出糖代谢改变的患者，一种潜在的治疗方法 目标，复苏后存活率最低。这项研究的父母奖试图定义如何 心脏骤停后的分子异质性和细胞紊乱会影响复苏后的结果。 相反，这项研究将集中在与免疫学有关的葡萄糖代谢的调节上。 功能，但提供独立的治疗机会。最近，许多人的兴趣集中在 关于人类棕色脂肪的代谢能力，因为这种组织具有很高的氧化代谢能力 像葡萄糖这样的燃料。棕色脂肪组织通过冷暴露而激活，并基于标准指南 心脏骤停的治疗包括治疗性低温。棕色脂肪组织在心脏中被激活 阻止患者，循环血糖水平的最佳调节尚不清楚。棕色脂肪组织可以 通过量化一种名为12，13-diHOME的循环脂质来测量，我们的初步研究表明 携带某些基因变异的患者会出现12，13-diHOME和血糖水平异常。我们 寻求确定棕色脂肪组织是否在心脏手术后调节葡萄糖代谢中起作用 我们提出的研究将与家长奖中的工作相吻合，以改善这些方面的结果 病人。为此，我们提出了一种创新的方法，其中我们测量了12，13-diHOME水平 具有和不具有单核苷酸多态性(SNP)的心脏骤停患者，我们和其他人都有 在EPHX2基因中发现，该基因编码12，13-diHOME生物合成酶。我们建议的工作 受益于团队科学工作，因为我们汇集了后科学领域的独特专业知识 复苏心脏骤停护理(SEDER)和棕色脂肪组织生物学(Lynes)。赛德医生有二十多个 有多年治疗心脏骤停患者的经验，莱恩斯博士也有超过15年的经验 在动物模型和患者样本中研究棕色脂肪组织生物学。赛德博士的经验 分离出有助于我们分析的临床和分子变量将是非常有价值的。莱恩斯博士 最初确定了我们建议测量的生物标记物12，13-diHOME，并发表了广泛的 关于这种脂质的研究范围。我们的研究也得益于团队科学方法，因为它试图 从患者的DNA到他们的循环代谢物，再到他们的表型 结果，所以我们需要一支完整的研究团队，他们可以与患者互动，进行样本采集， 数据收集、数据分析和结果解释。这始于我们接触患者的独特途径和 最初通过Seder博士获取和处理样本，然后进行血糖和血脂测量 莱恩斯博士的分析--他们的合作促进了这一过程的每一步。这项工程的完成 研究将确定心脏骤停后受益于治疗性低温的离散患者亚群， 并确定一种新的组织靶点，以减轻心脏骤停后血糖的变化，最终改善结果。

Project Summary Cardiac arrest has both a high incidence and high rate of mortality, with less than 7% of patients achieving a good neurological outcome. Patients that demonstrate alterations to glucose metabolism, a potential treatment target, have the lowest survival rates after resuscitation. The parent award for this study seeks to define how molecular heterogeneity and cellular disturbances after cardiac arrest affect post-resuscitation outcomes. Conversely, this study will focus on the regulation of glucose metabolism, which relates to immunological function, yet provides independent therapeutic opportunities. Recently, a great deal of interest has centered on the metabolic capacity of brown fat in humans, as this tissue has a high capacity for oxidizing metabolic fuels like glucose. Brown adipose tissue is activated by cold exposure, and standard guidelines-based treatment for cardiac arrest includes therapeutic hypothermia. Brown adipose tissue is activated in cardiac arrest patients, and optimal regulation of circulating glucose levels is unknown. Brown adipose tissue can be measured by quantifying a circulating lipid called 12,13-diHOME, and our preliminary studies show that patients harboring certain genetic variants have abnormal levels of 12,13-diHOME and blood glucose. We seek to determine whether brown adipose tissue plays a role in regulating glucose metabolism after cardiac arrest, and the studies we propose will dovetail with work in the parent award to improve outcomes in these patients. To this end we propose an innovative approach wherein we measure 12,13-diHOME levels in cardiac arrest patients with and without a single nucleotide polymorphism (SNP) that we and others have identified in the gene EPHX2, which codes for the 12,13-diHOME biosynthetic enzyme. Our proposed work benefits from a team science effort because we bring together unique expertise in the areas of post- resuscitation cardiac arrest care (Seder) and brown adipose tissue biology (Lynes). Dr. Seder has over twenty years of experience treating cardiac arrest patients, and Dr Lynes likewise has over 15 years of experience studying brown adipose tissue biology in animal models and patient samples. Dr. Seder’s experience in isolating clinical and molecular variables that could benefit our analysis will be highly valuable. Dr. Lynes originally identified the biomarker that we propose to measure, 12,13-diHOME, and has published a wide range of studies on this lipid. Our research also benefits from a team science approach because it seeks to span the full gamut from a patient’s DNA to their circulating metabolites and all the way to their phenotypic outcome, so we require a full team of researchers who can interact with patients, perform sample collection, data collection, data analysis and interpretation of results. This starts with our unique access to patients and initial specimen procurement and processing through Dr. Seder, followed by glucose and lipid measurement and analysis by Dr Lynes – their collaboration facilitating each step of this process. The completion of this study will define discrete patient subpopulations that benefit from therapeutic hypothermia after cardiac arrest, and identify a novel tissue target to mitigate post arrest alterations to glycemia, ultimately improving outcomes.