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

项目总结

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.