Metabolic alterations after aneurysmal subarachnoid hemorrhage

项目摘要 在美国，动脉瘤性蛛网膜下腔出血（aSAH）每年影响5万人，造成重大 发病率和死亡率。aSAH患者有发生继发性并发症的风险，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来预防DCI和晚期并发症 在aSAH之后。此外，aSAH患者易发生全身性并发症，涉及许多 包括心脏、肺和肾脏在内的器官系统，并且已知在 促炎细胞因子这项研究计划的目的是确定代谢变化， 发生在aSAH后及其与全身炎症的关系。在大脑受损后， 从氧化磷酸化（OXPHOS）到糖酵解的转变。这增加了对糖酵解的依赖 代谢是激活免疫效应细胞所必需的。我的初步结果显示 血浆中三羧酸（TCA）循环代谢物水平和糖酵解代谢物水平升高 aSAH患者富马酸盐和α-酮戊二酸盐水平较低， 结果。在目标1中，我们将使用质谱法回顾性地进行靶代谢组学研究。 从aSAH患者和对照组收集血浆样品。aSAH后的代谢特征将是 定义，生物信息学方法将用于研究哪些代谢物驱动促炎 细胞因子产生。在目标2中，将定量外周血单核细胞氧化代谢。 将对前瞻性采集的单核细胞进行代谢组学研究。外周血单核细胞 线粒体呼吸将与对照组和疾病严重程度进行比较。的 单核细胞内促炎细胞因子和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），以支持氧化代谢并减少单核细胞 将研究促炎细胞因子的产生。该项目将包括培训Gusdon博士， 进一步他的发展作为一个物理学家，科学家通过严格的课程开发中心， 临床和转化科学与生物医学信息学院。这将包括专门的统计 和生物信息学培训，并与转化和基础研究方面的专家进行重点指导。的 项目将在UTHealth的麦戈文医学院-纪念赫尔曼医院进行。

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.