Metabolic alterations after aneurysmal subarachnoid hemorrhage

动脉瘤性蛛网膜下腔出血后的代谢改变

基本信息

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
项目类别：
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

项目摘要

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 aSAH 患者有发生继发并发症的风险，例如尽管对动脉瘤破裂进行了充分的手术治疗，但仍出现血管痉挛和迟发性脑缺血（DCI）。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，已知其全身性升高本研究提案的目的是确定促炎细胞因子的代谢变化。发生在aSAH之后及其与全身炎症的关系发生在大脑之后。从氧化磷酸化 (OXPHOS) 转变为糖酵解导致的损伤，这增加了对糖酵解的依赖。我的初步结果显示，新陈代谢是免疫效应细胞激活所必需的。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 患者的富马酸和 α-酮戊二酸水平较低与功能较差相关。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。从 aSAH 患者和对照中收集血浆样本，分析 aSAH 后的代谢特征。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在目标 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中进行。与对照相比以及疾病严重程度，线粒体呼吸将被量化。单核细胞胞内促炎细胞因子与氧化代谢之间的关系，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调查促炎细胞因子的产生。该项目将包括对 Gusdon 博士进行培训。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。该项目将在 UTHealth 赫尔曼纪念医院的麦戈文医学院进行。