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%的患者达到了预期的效果。 良好的神经学结果。显示葡萄糖代谢改变的患者，一种潜在的治疗方法 目标，复苏后存活率最低。这项研究的父母奖旨在确定如何 心脏骤停后的分子异质性和细胞紊乱影响复苏后的结果。 相反，本研究将侧重于葡萄糖代谢的调节，这与免疫学有关。 功能，但提供独立的治疗机会。最近，大量的兴趣集中在 对人体棕色脂肪的代谢能力，因为这种组织具有高氧化代谢能力， 像葡萄糖这样的燃料。棕色脂肪组织被冷暴露激活， 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 停止患者，并且循环葡萄糖水平的最佳调节是未知的。棕色脂肪组织可以是 通过定量一种叫做12，13-diHOME的循环脂质来测量，我们的初步研究表明， 携带某些遗传变异的患者具有异常水平的12，13-diHOME和血糖。我们 试图确定棕色脂肪组织是否在心脏移植后调节葡萄糖代谢中起作用。 逮捕，我们提出的研究将与父母奖的工作相吻合，以改善这些结果 患者为此，我们提出了一种创新的方法，其中我们测量12，13-diHOME水平， 有和没有单核苷酸多态性（SNP）的心脏骤停患者， 在编码12，13-diHOME生物合成酶的基因EPHX 2中鉴定。我们建议的工作 受益于团队科学的努力，因为我们汇集了独特的专业知识，在后， 复苏心脏骤停护理（Seder）和棕色脂肪组织生物学（Lynes）。塞德医生有二十多个 Lynes博士有着多年治疗心脏骤停患者的经验， 在动物模型和病人样本中研究棕色脂肪组织生物学。Seder博士的经验 分离临床和分子变量，这可能有利于我们的分析，将是非常有价值的。莱恩斯医生 最初确定了我们建议测量的生物标志物12，13-diHOME，并发表了广泛的 对这种脂质的研究。我们的研究也受益于团队科学方法，因为它旨在 从病人的DNA到他们的循环代谢物，一直到他们的表型 结果，所以我们需要一个完整的研究人员团队，他们可以与患者互动，进行样本收集， 数据收集、数据分析和结果解释。这始于我们与患者的独特接触， 由Seder博士进行初始样本采集和处理，然后进行血糖和血脂测量 Lynes博士的分析-他们的合作促进了这一过程的每一步。完成这一 研究将确定从心脏骤停后治疗性低温中获益离散患者亚群， 并确定一种新的组织靶点，以减轻心脏骤停后的变化，最终改善预后。

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.