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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：开发一种有效针对多种病理机制的新治疗策略创伤性脑损伤（TBI）后的继发性脑损伤是临床的首要任务。 TBI 后神经血管炎症细胞的重新编程可能有助于细胞氧化/神经炎症应激并在早期触发和加速中发挥关键作用然而，最近的详细知识仍然未知。实验发现表明衣康酸是最丰富的三羧酸 (TCA) 之一由称为免疫反应基因 1 蛋白 (Irg-1) 的酶产生的循环中间体可能发挥作用作为调节代谢重编程的信号转导器，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传导通过保护线粒体氧化来调节小胶质细胞和脑血管内皮的通路磷酸化 (OXPHOS)，抑制糖酵解过度/NFκB 激活，并激活核因子 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）完整性破坏；这些行为交互地阻止了次级大脑；损伤并最终改善 TBI 的长期神经学结果。我们的初步数据非常有效。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、功能能量代谢测定的综合目标脑切片和分离细胞，并结合细胞特异性转基因和药理学，在目标 1 中，我们将研究分子病理学和神经学结果评估的作用。在目标 2 中，小胶质细胞 Irg-1/衣康酸对 TBI 后小胶质细胞促炎激活的调节作用。将研究脑血管内皮 Irg-1/衣康酸在 BBB 完整性调节中的作用在目标 3 中，我们将研究补充衣康酸在长期神经系统结果中的作用。小鼠 TBI 后的研究将提供对动态的详细见解。炎症小胶质细胞和脑内皮的生物能量学/代谢重编程，阐明 Irg-1/衣康酸在调节代谢重编程和相关神经血管中的作用 TBI 后的炎症机制。