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: 10528484
• 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/10528484
• 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; Dedications; Development; Disease; Educational Curriculum; Effector Cell; Flow Cytometry; Fumarates; Genus Hippocampus; Glutamine; Glycolysis; Heart; Hemorrhage; Hospitals; Hour; IL8 gene; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; 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; Predisposition; 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; 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.

项目概要 在美国，动脉瘤性蛛网膜下腔出血 (aSAH) 每年影响 50,000 人，造成严重后果 发病率和死亡率。 aSAH 患者有发生继发并发症的风险，例如 血管痉挛和迟发性脑缺血（DCI）。尽管对动脉瘤破裂进行了充分的手术治疗 和积极的医疗管理，很少有有效的治疗方法可以预防 DCI 和晚期并发症 在aSAH之后。此外，aSAH 患者容易出现涉及多种全身并发症。 器官系统，包括心脏、肺和肾脏，已知其全身性升高 促炎细胞因子。本研究计划的目的是定义代谢变化 发生在 aSAH 后及其与全身炎症的关系。大脑发生明显的代谢变化 从氧化磷酸化（OXPHOS）转变为糖酵解的损伤。这增加了对糖酵解的依赖 免疫效应细胞的激活需要新陈代谢。我的初步结果显示下降 血浆中三羧酸 (TCA) 循环代谢物的水平和糖酵解代谢物的水平增加 aSAH 患者。富马酸和α-酮戊二酸水平较低与功能较差相关 结果。在目标 1 中，我们将使用质谱法回顾性地进行目标代谢组学 收集 aSAH 患者和对照患者的血浆样本。 aSAH 后的代谢特征将是 已定义，生物信息学方法将用于研究哪些代谢物驱动促炎症 细胞因子的产生。在目标 2 中，将对外周血单核细胞氧化代谢进行量化。 代谢组学将从前瞻性收集的单核细胞中进行。外周血单核细胞 与对照相比以及疾病严重程度，线粒体呼吸将被量化。这 单核细胞胞内促炎细胞因子与氧化代谢的关系，包括 将研究线粒体膜电位。代谢靶向治疗的能力 （二甲双胍、富马酸二甲酯和谷氨酰胺）促进氧化代谢并减少单核细胞 将研究促炎细胞因子的产生。该项目将包括对 Gusdon 博士的培训 通过该中心开发的严格课程，进一步促进他作为一名医师科学家的发展 临床和转化科学以及生物医学信息学院。这将包括专门的统计 生物信息学培训以及转化和基础研究专家的重点指导。这 项目将在 UTHealth 赫尔曼纪念医院的麦戈文医学院进行。