Oxidative Lipidomics in Pediatric Traumatic Brain Injury

氧化脂质组学在小儿创伤性脑损伤中的应用

基本信息

批准号：
10844023
负责人：
Hülya Bayir
金额：
$ 33.61万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10844023
关键词：
Acute Acyltransferase Adult Affinity Anti-Inflammatory Agents Antioxidants Apoptotic Arachidonate 15-Lipoxygenase Arachidonic Acids Biochemical Reaction Brain Brain Injuries Cardiolipins Cause of Death Cessation of life Child Childhood Injury Chronic Clinical Trials Coenzyme A Ligases Collaborations Complex Data Endoplasmic Reticulum Enzymes Esterification Event Family member Free Radical Scavengers Free Radicals Funding Generations Glutathione Hospitalization Hydrogen Peroxide Hydrolysis Hydroxides Image Induction of Apoptosis Inflammatory Response Injury Innovative Therapy Iron Link Lipid Peroxidation Lipoxygenase Inhibitors Lysophosphatidylcholines Mechanics Membrane Mitochondria Morbidity - disease rate National Center for Advancing Translational Sciences Nature Neurological outcome Neurons Oxidation-Reduction Oxidative Stress Pathogenicity Pathway interactions Pattern Peroxidases Phosphatidylethanolamine Phosphatidylethanolamine Binding Protein Phospholipase Phospholipids Proteins Rattus Reduced Glutathione Role Scaffolding Protein Signal Transduction Source Stretching Substrate Specificity Sulfhydryl Compounds System TBI treatment Technology Testing Therapeutic Therapeutic Uses Translations Trauma Traumatic Brain Injury United States National Institutes of Health Work adduct baicalein catalyst cognitive function controlled cortical impact cytochrome c design drug discovery experimental study glutathione peroxidase improved outcome inhibitor lipidomics liquid chromatography mass spectrometry mortality neuron apoptosis neuron loss neuroprotection new therapeutic target novel therapeutics oxidation pediatric traumatic brain injury peroxidation postnatal preference preservation prevent protein complex small molecule small molecule inhibitor standard care targeted treatment

项目摘要

Each year in the US, severe TBI in children results in ∼7400 deaths and 60 000 hospitalizations. Fifty percent of surviving children with severe TBI have poor neurological outcome at six months. Severe TBI in children is thus a critical problem in desperate need of impactful therapies. Free radicals and oxidative stress have been uniformly accepted as universal pathogenic mechanisms of TBI prompting therapeutic use of antioxidants. Invariably, clinical trials of non-specific free radical scavengers/antioxidants failed. This suggests that true sources and mechanisms of TBI redox disbalance remain undefined, and represent a potential therapeutic opportunity. During the previous funding period we showed that lipid peroxidation after TBI in immature brain occurs as a result of controlled enzymatic reactions. We discovered that peroxidation of mitochondrial phospholipid cardiolipin (CL) represents a required stage of neuronal apoptosis after TBI in postnatal day (PND) 17 rats. We identified cytochrome c as a catalyst of CL peroxidation and showed that a mitochondria- targeted inhibitor of CL peroxidation suppressed TBI-induced apoptosis and preserved cognitive function in PND17 rats. Our latest work identified highly selective oxidation of arachidonic acid (AA) containing phosphatidylethanolamines (PE) by 15 lipoxygenase (15LOX) to be causative to ferroptosis. We discovered that PE binding protein 1 (PEBP1) complexes with 15LOX and changes its substrate specificity from free AA to AA esterified into PE to generate hydroperoxy-AA-PE death signals. Normally hydroperoxy-AA-PE are eliminated by combined action of glutathione peroxidase 4 (GPX4)/glutathione (GSH). Immature brain has lower GSH levels and GPX activity vs adult brain thus could be more vulnerable to ferroptosis upon injury. Indeed our preliminary data show that TBI leads to marked increase in expression and activity of 15LOX, and accumulation of oxidized AA-PE in PND17 rat brain. Furthermore, preliminary data indicate that inhibition of AA-PE oxidation suppresses TBI-induced neuronal death and preserves cognitive function. Thus, we hypothesize that generation of oxidized AA-PE by 15LOX/PEBP1 complex leads to neuronal death and represents a new target for drug discovery leading to innovative therapies in pediatric TBI. We propose to test our hypothesis in three Specific Aims. Aim 1 will determine the degree, spatial and temporal pattern of 15LOX/PEBP1 complex formation and AA-PE oxidation after TBI. Aim 2 will investigate the mechanisms of AA-PE oxidation in TBI-induced neuronal death. Aim 3 will design and investigate the mechanism of action and neuroprotective potential of small-molecule regulators of 15LOX and 15LOX/PEBP1 activity in TBI. These studies will employ powerful lipidomics and oxidative lipidomics technology to provide important mechanistic information on the role of PE oxidation in neuronal ferroptosis after pediatric TBI. The ability to selectively modulate PE oxidation, a critical early event in the mechanism of ferroptosis, could lead to targeted therapies for TBI and ultimately improve outcome for children after brain injury.

在美国，严重的 TBI 每年导致约 7400 人死亡，60 000 人住院治疗。患有严重 TBI 的幸存儿童在六个月时神经功能状况不佳。因此，自由基和氧化应激是迫切需要有效治疗的一个关键问题。普遍认为 TBI 的普遍致病机制促使抗氧化剂的治疗使用。非特异性自由基清除剂/抗氧化剂的临床试验总是失败，这表明这是正确的。 TBI 氧化还原失衡的来源和机制仍不清楚，但代表了一种潜在的治疗方法在之前的资助期间，我们发现未成熟大脑中 TBI 后的脂质过氧化。我们发现线粒体的过氧化反应是受控酶反应的结果。磷脂心磷脂 (CL) 代表出生后 TBI 后神经元凋亡的必要阶段 (PND) 17 只大鼠，我们鉴定出细胞色素 c 是 CL 过氧化的催化剂，并表明线粒体- CL过氧化的靶向抑制剂抑制了TBI诱导的细胞凋亡并保留了认知功能我们最新的工作鉴定了 PND17 大鼠中含有的花生四烯酸 (AA) 的高度选择性氧化。我们发现 15 脂氧合酶 (15LOX) 产生的磷脂酰乙醇胺 (PE) 会导致铁死亡。 PE 结合蛋白 1 (PEBP1) 与 15LOX 复合，并将其底物特异性从游离 AA 改变为 AA酯化到PE中产生氢过氧-AA-PE死亡信号通常氢过氧-AA-PE是。通过谷胱甘肽过氧化物酶 4 (GPX4)/谷胱甘肽 (GSH) 的联合作用消除未成熟的大脑。与成人大脑相比，GSH 水平和 GPX 活性较低，因此在受伤时更容易出现铁死亡。事实上，我们的初步数据表明，TBI 导致 15LOX 的表达和活性显着增加，并且 PND17 大鼠脑中氧化 AA-PE 的积累此外，初步数据表明，抑制 AA-PE 氧化可抑制 TBI 诱导的神经元死亡并保留认知功能。促进了 15LOX/PEBP1 复合物生成氧化 AA-PE 导致神经元死亡代表了药物发现的新目标，导致儿童 TBI 的创新疗法。我们建议进行测试。我们在三个具体目标 1 中的假设将决定的程度、空间和时间模式。目标 2 将研究 TBI 后 15LOX/PEBP1 复合物的形成和 AA-PE 氧化的机制。 AA-PE 氧化在 TBI 诱导的神经元死亡中的作用目标 3 将设计和研究其作用机制。 15LOX 和 15LOX/PEBP1 活性的小分子调节剂在 TBI 中的神经保护潜力。研究将采用强大的脂质组学和氧化脂质组学技术来提供重要的机制关于 PE 氧化在儿科 TBI 后神经元铁死亡中的作用的信息调节 PE 氧化（铁死亡机制中的一个关键早期事件）可能会导致靶向治疗治疗 TBI 并最终改善脑损伤后儿童的预后。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Successive High-Resolution (H2O)n-GCIB and C60-SIMS Imaging Integrates Multi-Omics in Different Cell Types in Breast Cancer Tissue.

连续高分辨率 (H2O)n-GCIB 和 C60-SIMS 成像集成了乳腺癌组织中不同细胞类型的多组学。

DOI：
发表时间：
2021-06-15
期刊：
影响因子：
7.4
作者：
Tian, Hua;Sparvero, Louis J;Anthonymuthu, Tamil Selvan;Sun, Wan;Amoscato, Andrew A;He, Rong;Bayır, Hülya;Kagan, Valerian E;Winograd, Nicholas
通讯作者：
Winograd, Nicholas

Integrated -omics approach reveals persistent DNA damage rewires lipid metabolism and histone hyperacetylation via MYS-1/Tip60.

综合组学方法揭示了持续性 DNA 损伤通过 MYS-1/Tip60 重新连接脂质代谢和组蛋白过度乙酰化。

DOI：
发表时间：
2022-02-18
期刊：
影响因子：
13.6
作者：
Hamsanathan, Shruthi;Anthonymuthu, Tamil;Han, Suhao;Shinglot, Himaly;Siefken, Ella;Sims, Austin;Sen, Payel;Pepper, Hannah L;Snyder, Nathaniel W;Bayir, Hulya;Kagan, Valerian;Gurkar, Aditi U
通讯作者：
Gurkar, Aditi U

Cardiolipin-Dependent Mitophagy Guides Outcome after Traumatic Brain Injury.

心磷脂依赖性线粒体自噬指导创伤性脑损伤后的结果。

DOI：
发表时间：
2019-03-06
期刊：
影响因子：
0
作者：
Chao, Honglu;Lin, Chao;Zuo, Qiang;Liu, Yinlong;Xiao, Mengqing;Xu, Xiupeng;Li, Zheng;Bao, Zhongyuan;Chen, Huimei;You, Yongping;Kochanek, Patrick M;Yin, Huiyong;Liu, Ning;Kagan, Valerian E;Bayır, Hülya;Ji, Jing
通讯作者：
Ji, Jing

Mitochondrial damage & lipid signaling in traumatic brain injury.

线粒体损伤

DOI：
发表时间：
2020
期刊：
影响因子：
5.3
作者：
Lamade, Andrew M;Anthonymuthu, Tamil S;Hier, Zachary E;Gao, Yuan;Kagan, Valerian E;Bayır, Hülya
通讯作者：
Bayır, Hülya

Elimination of the unnecessary: Intra- and extracellular signaling by anionic phospholipids.

消除不必要的：阴离子磷脂的细胞内和细胞外信号传导。

DOI：
发表时间：
2017-01-15
期刊：
影响因子：
3.1
作者：
Kagan, Valerian E;Bayır, Hülya;Tyurina, Yulia Y;Bolevich, Sergey B;Maguire, John J;Fadeel, Bengt;Balasubramanian, Krishnakumar
通讯作者：
Balasubramanian, Krishnakumar