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

急性护理研究和农村差异生物医学卓越研究中心

基本信息

批准号：
10854114
负责人：
Douglas B Sawyer
金额：
$ 52.66万
依托单位：
MAINEHEALTH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-10 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10854114
关键词：
Adult Affect Alleles Anabolism Animal Model Area Award Biological Markers Biology Blood Glucose Body Temperature Body mass index Brain Injuries Brown Fat Cardiopulmonary Resuscitation Caring Cause of Death Centers of Research Excellence Clinical Clinical Research Code Collaborations Complications of Diabetes Mellitus Coupled DNA Data Data Analyses Data Collection Data Set Discrimination Enzyme-Linked Immunosorbent Assay Enzymes Epoxide hydrolase Fatty acid glycerol esters Genes Genetic Polymorphism Genotype Glucose Glycols Guidelines Health Heart Arrest Heterogeneity Hour Human Hyperglycemia Incidence Insulin Resistance Ischemia Ischemic Brain Injury Lipids Liquid Chromatography Mass Spectrum Analysis Measurement Measures Mediating Mediation Mediator Metabolic Molecular Monitor Multiple Organ Failure Neurological outcome Organ Outcome Parents Patients Persons Phenotype Play Process Publishing Records Regression Analysis Regulation Reperfusion Injury Reperfusion Therapy Reporting Research Research Personnel Resuscitation Risk Role Sampling Science Severities Single Nucleotide Polymorphism Single Nucleotide Polymorphism in Coding Sequence Specimen Survival Rate Sympathetic Nervous System Temperature Testing Therapeutic Thermogenesis Tissues Triglycerides Type 2 diabetic Work acute care blood glucose regulation cold temperature diabetic patient experience genetic variant glucose metabolism hypercholesterolemia immune function improved outcome innovation insulin sensitivity interest lipidomics metabolic phenotype mortality natural hypothermia neuroprotection novel organ injury patient population patient stratification patient subsets rural disparities sample collection uncoupling protein 1

项目摘要

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.

项目概要心脏骤停的发生率和死亡率都很高，只有不到 7% 的患者能够达到心脏骤停的标准。表现出葡萄糖代谢改变的患者，这是一种潜在的治疗方法。这项研究的家长奖旨在定义如何实现复苏后的最低存活率。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。间接地，本研究将重点关注与免疫学相关的葡萄糖代谢的调节功能，但提供独立的治疗机会，最近引起了极大的兴趣。影响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葡萄糖等燃料会因寒冷暴露而被激活，并且基于标准指南。心脏骤停的治疗包括治疗性低温治疗，激活心脏中的棕色脂肪组织。逮捕患者，并且循环葡萄糖水平的最佳调节尚不清楚。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遗传变异的患者的 12,13-diHOME 和血糖水平异常。试图确定棕色脂肪组织是否在心脏术后葡萄糖代谢调节中发挥作用逮捕，我们提出的研究将与家长奖的工作相结合，以改善这些方面的结果为此，我们提出了一种测量患者体内 12,13-diHOME 水平的创新方法。具有或不具有我们和其他人拥有的单核苷酸多态性 (SNP) 的心脏骤停患者在基因 EPHX2 中鉴定出，该基因编码 12,13-diHOME 生物合成酶。受益于团队科学努力，因为我们汇集了后领域的独特专业知识 Seder 博士拥有 20 多年的心脏骤停护理 (Seder) 和棕色脂肪组织生物学 (Lynes) 经验。多年治疗心脏骤停患者的经验，Lynes 医生同样拥有超过 15 年的经验 Seder 博士在动物模型和患者样本中研究棕色脂肪组织生物学。莱恩斯博士指出，分离出有利于我们分析的临床和分子变量将非常有价值。最初确定了我们建议测量的生物标志物 12,13-diHOME，并发表了广泛的我们对这种脂质的一系列研究也受益于团队科学方法，因为它寻求涵盖从患者 DNA 到循环代谢物直至表型的整个范围结果，因此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始于我们对患者和结果的独特访问。通过 Dr. Seder 进行初始样本采购和处理，然后进行葡萄糖和脂质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。研究将确定心脏骤停后受益于低温治疗的离散患者亚群，并确定一个新的组织靶点来减轻逮捕后血糖的变化，最终改善结果。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Letter to the Editor: "Midodrine to liberate ICU patients from intravenous vasopressors: Another negative fixed-dose trial".

DOI：
10.1016/j.jcrc.2022.153995
发表时间：
2022-06
期刊：
JOURNAL OF CRITICAL CARE
影响因子：
3.7
作者：
Riker, Richard R.;Gagnon, David J.
通讯作者：
Gagnon, David J.

Anti-fibrinolytic agent tranexamic acid suppresses the endotoxin-induced expression of Tnfα and Il1α genes in a plasmin-independent manner.

抗纤溶剂氨甲环酸以纤溶酶独立的方式抑制内毒素诱导的 Tnfα 和 Il1α 基因的表达。

DOI：
10.1111/trf.17353
发表时间：
2023
期刊：
Transfusion
影响因子：
2.9
作者：
Kacer,Doreen;Machnitzky,Eva;Fung,Angus;Greene,Autumn;Carter,Damien;Rappold,Joseph;Prudovsky,Igor
通讯作者：
Prudovsky,Igor

Telemedicine Consultation to Assess Neonatal Encephalopathy in Rural Community Hospitals and Tertiary Care Centers.