Metabolic alterations after aneurysmal subarachnoid hemorrhage

动脉瘤性蛛网膜下腔出血后的代谢改变

• 批准号: 10371769
• 负责人: Aaron Mark Gusdon
• 金额: $ 18.55万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371769
• 关键词: Affect; Aneurysmal Subarachnoid Hemorrhages; Anti-Inflammatory Agents; Attenuated; Basic Science; Bioinformatics; Biological Assay; Blood specimen; Brain Injuries; CCL3 gene; Cell Respiration; Cerebral Ischemia; Citrates; Citric Acid Cycle; Clinical; Clinical Sciences; Data; Development; Disease; Educational Curriculum; Effector Cell; Flow Cytometry; Fumarates; Genus Hippocampus; Glutamine; Glycolysis; Heart; Hemorrhage; Hospitals; Hour; IL8 gene; Impairment; Individual; Inflammation; Inflammatory; Innate Immune System; Interleukin-1; Interleukin-6; Kidney; Leukocytes; Lung; Mass Spectrum Analysis; Measures; Medical; Membrane Potentials; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Metformin; Methods; Mitochondria; Morbidity - disease rate; Operative Surgical Procedures; Outcome; Oxidative Phosphorylation; Patients; Peripheral; Persons; Phenotype; Physicians; Plasma; Production; Research Proposals; Respiration; Risk; Rupture; Ruptured Aneurysm; Sampling; Schools; Scientist; Sepsis; Severities; Severity of illness; TNF gene; Therapeutic Intervention; Time; Training; Translational Research; Tricarboxylic Acids; Validation; Vasospasm; alpha ketoglutarate; base; biomedical informatics; body system; clinical center; cohort; cytokine; effective therapy; extracellular; fatty acid oxidation; functional outcomes; immune activation; improved; improved outcome; machine learning model; medical schools; metabolomics; mitochondrial membrane; monocyte; mortality; outcome prediction; peripheral blood; predict clinical outcome; predictive modeling; prevent; prospective; response; systemic inflammatory response; targeted treatment

PROJECT SUMMARY Aneurysmal subarachnoid hemorrhage (aSAH) affects 50,000 people per year in the U.S., causing significant morbidity and mortality. Patients with aSAH are at risk of developing secondary complications such as vasospasm and delayed cerebral ischemia (DCI). Despite adequate surgical treatment of aneurysmal rupture and aggressive medical management, few effective treatments exist to prevent DCI and late complications after aSAH. Furthermore, patients with aSAH are susceptible to systemic complications involving numerous organ systems including the heart, lungs, and kidneys and are known to have systemic elevations in proinflammatory cytokines. The purpose of this research proposal is to define the metabolic changes that occur after aSAH and their relationship to systemic inflammation. Marked metabolic changes occur after brain injury with a shift from oxidative phosphorylation (OXPHOS) to glycolysis. This increased reliance on glycolytic metabolism is required for the activation of immune effector cells. My preliminary results show decreased levels of tricarboxylic acid (TCA) cycle metabolites and increased levels of glycolytic metabolites in the plasma of aSAH patients. Lower levels of fumarate and α-ketoglutarate are associated with worse functional outcomes. In Aim 1, we will use mass spectrometry to perform target metabolomics on retrospectively collected plasma samples from patients with aSAH and controls. A metabolic signature after aSAH will be defined, and bioinformatics methods will be used to investigate which metabolites drive proinflammatory cytokine production. In Aim 2, peripheral blood monocyte oxidative metabolism will be quantified. Metabolomics will be performed from prospectively collected monocytes. Peripheral blood monocyte mitochondrial respiration will be quantified compared with controls and across disease severity. The relationship between the monocyte intracellular proinflammatory cytokines and oxidative metabolism including mitochondrial membrane potential will be investigated. The ability of metabolically targeted treatments (metformin, dimethylfumarate, and glutamine) to bolster oxidative metabolism and decrease monocyte proinflammatory cytokine production will be investigated. This project will include training for Dr. Gusdon to further his development as a physician-scientist through a rigorous curriculum developed in the Center for Clinical and Translational Sciences and School of Biomedical Informatics. This will include dedicated statistical and bioinformatics training and focused mentorship with experts in translational and basic research. The project will be performed at the McGovern Medical School at UTHealth- Memorial Hermann Hospital.

项目摘要 动脉瘤性蛛网膜下腔出血（ASAH）每年在美国影响50,000人，导致重大 发病率和死亡率。 ASAH患者有患次要并发症的风险，例如 血管痉挛和延迟的脑缺血（DCI）。尽管手术治疗动脉瘤破裂 和积极的医疗管理，几乎没有有效的治疗方法可以防止DCI和晚期并发症 朝拜之后。此外，ASAH患者容易受到全身并发症的影响 包括心脏，肺和儿童在内的器官系统，众所周知 促炎细胞因子。该研究建议的目的是定义代谢变化 发生在ASAH之后及其与系统性炎症的关系。大脑后发生明显的代谢变化 从氧化磷酸化（OXPHOS）转移到糖酵解的损伤。这增加了糖酵解的保留率 激活免疫效应细胞需要代谢。我的初步结果显示 三核酸（TCA）循环代谢产物的水平和等离子体中糖酵解代谢水平的水平增加 屁股患者。较低水平的富马酸盐和α-酮戊二酸与功能较差有关 结果。在AIM 1中，我们将使用质谱法对追溯性执行目标代谢组学 收集了来自ASAH和对照患者的血浆样品。 Asah之后的代谢签名将是 定义，生物信息学方法将用于研究哪种代谢物驱动促炎性 细胞因子产生。在AIM 2中，将量化外周血单核细胞氧化代谢。 代谢组学将从前瞻性收集的单核细胞进行。外周血单核细胞 与对照组和跨疾病严重程度相比，线粒体呼吸将被定量。这 单核细胞内促炎细胞因子与氧化代谢之间的关系 线粒体膜电位将被研究。代谢靶向治疗的能力 （二甲双胍，二甲基甲酸和谷氨酰胺）以增强氧化物代谢并减少单核细胞 将研究促炎性细胞因子的产生。该项目将包括Gusdon博士的培训 进一步通过在中心开发的严格课程来进一步发展作为身体科学家 临床和转化科学以及生物医学信息学学校。这将包括专门的统计数据 以及与转化和基础研究专家的生物信息学培训和专注于精神训练。这 项目将在Uthealth-Memorial Hermann医院的McGovern医学院举行。