Role of Irg-1/itaconate in modulating secondary brain damage after traumatic brain injury in mice

Irg-1/衣康酸在调节小鼠脑外伤后继发性脑损伤中的作用

• 批准号: 10594260
• 负责人: XIAOYING WANG
• 金额: $ 43.46万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594260
• 关键词: Acceleration; Acute; Biochemical; Bioenergetics; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Caprylates; Cell Separation; Cells; Central Nervous System Diseases; Cerebrum; Citric Acid Cycle; Clinical; Data; Development; Endothelial Cells; Endothelium; Energy Metabolism; Enzymes; Extravasation; Genes; Genus Hippocampus; Glucose; Glutamine; High-Throughput RNA Sequencing; Homeostasis; Immune; Inflammatory; Inflammatory Response; Injury; Knowledge; Mediating; Metabolic; Metabolism; Microglia; Mitochondria; Molecular; Mus; Nerve Degeneration; Neurologic Deficit; Neurological outcome; Nuclear; Outcome Assessment; Oxidative Phosphorylation; Pathologic; Pathway interactions; Phase; Phenotype; Play; Protein Overexpression; Proteins; Role; Signal Pathway; Signal Transduction; Slice; Sodium; Stress; Supplementation; Testing; Transcriptional Activation; Transducers; Transgenic Organisms; Traumatic Brain Injury; Vascular Endothelium; blood-brain barrier permeabilization; brain tissue; cerebrovascular; effective intervention; fatty acid metabolism; glial activation; immunoregulation; improved; insight; metabolomics; mitochondrial permeability transition pore; molecular pathology; neuroinflammation; neurovascular; new therapeutic target; novel; novel therapeutic intervention; oxidation; pharmacologic; preservation; prevent; single-cell RNA sequencing; stable isotope; transcription factor; transcriptomics

Project Summary: The development of a novel therapeutic strategy to effectively target multiple pathological mechanisms of secondary brain damage after traumatic brain injury (TBI) is a top clinical priority. The metabolic reprogramming of neurovascular inflammatory cells after TBI may contribute to the cellular oxidative/neuroinflammatory stresses and play critical roles in the early triggering and acceleration of secondary brain injury cascades. However, the detailed knowledge remains largely unknown. Recent experimental discoveries demonstrate that itaconate, one of the most abundant tricarboxylic acids (TCA) cycle intermediates, produced by an enzyme called immune-responsive gene 1 protein (Irg-1), may function as a signaling transducer in modulating the metabolic reprogramming. Our central hypothesis is that the Irg- 1/itaconate modulates the metabolic reprogramming and thus controls neurovascular inflammatory signaling pathways of the microglia and the cerebrovascular endothelium by preserving mitochondria oxidative phosphorylation (OXPHOS), suppressing hyperglycolysis/NFκB activation, and activating nuclear factor E2- related factor 2 (Nrf2), which results in the inhibition of microglial activation-associated neuroinflammation, and blood-brain barrier (BBB) integrity disruption; these actions interactively prevent the secondary brain damage and ultimately improve the long-term neurological outcome of TBI. Our preliminary data are highly supportive of our proposed hypotheses and experimental approaches. In this project, we will pursue three integrated aims using bioenergetics/metabolomics and transcriptomics, functional energy metabolic assay of brain slices and isolated cells, and in combination with cell-specific transgenic and pharmacological, molecular pathology, and neurological outcome assessments. In Aim 1, we will investigate the role of microglial Irg-1/itaconate in the modulation of microglial pro-inflammatory activation after TBI. In Aim 2, we will investigate the role of cerebrovascular endothelial Irg-1/itaconate in the modulation of BBB integrity after TBI. In Aim 3, we will investigate the role of itaconate supplementation in long-term neurological outcomes after TBI in mice. The proposed studies will provide detailed insights into the dynamic bioenergetics/metabolic reprogramming of inflammatory microglia and cerebral endothelium, elucidate the role of Irg-1/itaconate in modulating the metabolic reprogramming, and associated neurovascular inflammatory mechanisms after TBI.

项目总结： 一种新的治疗策略的发展，以有效地针对多种病理机制 颅脑损伤后继发性脑损伤是临床的重中之重。新陈代谢 脑外伤后神经血管炎症细胞的重新编程可能对细胞 氧化/神经炎性应激，并在早期触发和加速 继发性脑损伤层出不穷。然而，详细的信息在很大程度上仍然是未知的。近期 实验发现衣康酸，一种最丰富的三元酸(TCA) 由一种名为免疫反应基因1蛋白(IRG-1)的酶产生的周期中间产物可能起作用 作为调节新陈代谢重编程的信号转导。我们的中心假设是IRG- 1/衣康酸调节代谢重编程，从而控制神经血管炎症信号 线粒体氧化保存对小胶质细胞和脑血管内皮细胞的影响 磷酸化(OXPHOS)，抑制高糖酵解/核因子κB激活，激活核因子E2- 相关因子2(Nrf2)，可抑制小胶质细胞激活相关的神经炎症； 和血脑屏障(BBB)的完整性破坏；这些行为交互作用地防止继发性大脑 损害并最终改善脑外伤的长期神经结局。我们的初步数据显示 支持我们提出的假设和实验方法。在这个项目中，我们将追求三个 使用生物能量学/代谢组学和转录组学、功能能量代谢分析的综合目标 脑片和分离的细胞，并结合细胞特异性转基因和药理学， 分子病理学和神经学结果评估。在目标1中，我们将调查 小胶质细胞IRG-1/衣康酸在脑损伤后小胶质细胞促炎活化中的调节作用在目标2中，我们 将探讨脑血管内皮细胞IRG-1/衣康酸在脑出血后血脑屏障完整性调节中的作用 TBI。在目标3中，我们将调查衣康酸补充剂在长期神经预后中的作用。 小鼠脑损伤后。拟议的研究将提供对动态的详细见解 炎性小胶质细胞和脑内皮细胞的生物能量学/代谢重编程，阐明 IRG-1/衣康酸在调节代谢重编程及相关神经血管中的作用 创伤性脑损伤后的炎症机制。