Metabolic alterations after aneurysmal subarachnoid hemorrhage

项目总结 在美国，动脉瘤性蛛网膜下腔出血(ASAH)每年影响5万人，造成显著的 发病率和死亡率。患有ASAH的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适当的外科治疗 和积极的医疗管理，几乎没有有效的治疗方法来预防DCI和晚期并发症 在浅草之后。此外，ASAH患者容易出现系统性并发症，涉及许多 器官系统，包括心脏，肺和肾脏，已知在 促炎细胞因子。这项研究提案的目的是定义 发生在ASAH之后及其与全身炎症的关系。脑损伤后发生显著的代谢变化 损伤，从氧化磷酸化(OXPHOS)转变为糖酵解。这增加了对糖酵解的依赖 新陈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)循环代谢产物水平和糖酵解代谢产物水平升高 ASAH患者的比例。较低的富马酸和α-酮戊二酸水平与较差的功能有关 结果。在目标1中，我们将使用质谱仪回溯性地进行靶向代谢组学 采集ASAH患者和对照组的血浆样本。ASAH之后的代谢特征将是 将使用已定义的生物信息学方法来研究哪些代谢物驱动促炎 细胞因子的产生。在目标2中，将量化外周血单核细胞的氧化代谢。 代谢组学将从预期收集的单核细胞中进行。外周血单核细胞 线粒体呼吸将与对照组和不同疾病严重程度进行量化。这个 单核细胞胞内致炎细胞因子与氧化代谢的关系 将对线粒体膜电位进行研究。代谢靶向治疗的能力 (二甲双胍、富马酸二甲酯和谷氨酰胺)促进氧化代谢和减少单核细胞 将对促炎症细胞因子的产生进行调查。该项目将包括对古斯顿博士的培训，以 通过中心制定的严格课程，进一步发展成为一名内科科学家 临床与转化科学与生物医学信息学学院。这将包括专门的统计数据 以及生物信息学培训，并与翻译和基础研究方面的专家进行重点指导。这个 该项目将在德克萨斯大学健康纪念赫尔曼医院的麦戈文医学院进行。

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.