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：
8279412
负责人：
Hülya Bayir
金额：
$ 32.48万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8279412
关键词：
Acetylcysteine Acidosis Acute Address Adult Alzheimer&apos s Disease Antioxidants Apoptosis Apoptotic Binding Biochemistry Biophysics Blood Vessels Brain Brain Injuries Calcium Cardiolipins Caspase Cause of Death Cell Death Cell Survival Cell membrane Cell physiology Cells Cerebral cortex Cerebrospinal Fluid Cessation of life Chemistry Child Clinic Clinical Complex Critical Care Cytochrome c Peroxidase Cytosol DNA strand break Data Development Diabetes Mellitus Diet Disease Esters Event Fatty Acids Female Free Radicals Functional disorder Gender Generations Genomic Instability Glutamates Glutathione Homeostasis Human Hydrogen Peroxide In Vitro Infant Inflammation Injury Inner mitochondrial membrane Intracranial Hypertension Knowledge Lead Link Lipids Mediating Medicine Membrane Lipids Mitochondria Modeling Modification Molecular Monitor Morbidity - disease rate Neuronal Injury Neurons Outcome Oxidation-Reduction Oxidative Stress Oximes Participant Pathway interactions Patients Pattern Phagocytosis Phosphatidylserines Phospholipids Post-Translational Protein Processing Predisposition Process Production Property Proteins Proteomics Rattus Reactive Oxygen Species Refractory Regulation Research Role Sampling Signal Pathway Signal Transduction Signaling Molecule Stimulus Stretching System TBI Patients Techniques Technology Testing Therapeutic Therapeutic Effect Tissues Translational Research Trauma Traumatic Brain Injury ascorbate base bench to bedside brain tissue cell injury clinical effect controlled cortical impact cytochrome c design dietary antioxidant improved in vivo in vivo Model infant brain injury insight male mortality natural hypothermia neuron apoptosis novel osteogenic oxidation pediatric traumatic brain injury prevent protein protein interaction research study therapy development tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Trauma in infants and children remains a significant cause of morbidity and mortality. Severe traumatic brain injury (TBI) is an important participant in this mortality and associated morbidity. Apoptosis contributes to neuronal death after TBI. The release of Cytochrome c (cyt c) from inner mitochondrial space of the mitochondria is a critical early event in mitochondrially mediated apoptotic cell death. Upon extrusion into the cytosol, cyt c activates initiator and effector caspase cascades responsible for apoptosis. Recently we have shown novel redox catalytic properties of cyt c realized though its interactions with CL in mitochondria and PS in plasma membrane resulting in their selective oxidation. The resulting products, CL and PS hydroperoxides act as important signals in two apoptotic pathways regulation of release of apoptotic factors from mitochondria into cytosol, and externalization of PS marking apoptotic cells for phagocytosis. Our hypothesis is that TBI initiates excessive production of ROS and selective early oxidation of phospholipids with accumulation of oxidized CL triggering release of pro-apoptotic factors from mitochondria. As a consequence, we predict that TBI induced CL oxidation and apoptosis can be prevented by antioxidant strategies and treatments decreasing susceptibility of CL to oxidation by dietary manipulation of its fatty acid residues. We will utilize a comprehensive approach from in vitro (stretch injury of neurons) and in vivo models (controlled cortical impact (CCI) model in post-natal day (PND) 17 rats) to clinical pediatric TBI to address the following specific aims: 1) Determine the degree, spatial and temporal pattern of ROS production, antioxidant depletion and CL oxidation in immature brain after CCI 2) Investigate whether gender influences ROS production, antioxidant depletion and CL oxidation in immature brain after TBI and in neurons after stretch-injury and glutamate exposure. 3) Determine the potential of antioxidants and dietary manipulation to inhibit mitochondrial CL oxidation and protect against apoptosis in immature brain after TBI and in neurons after stretch injury and glutamate exposure glutamate exposure 4) Design and investigate mechanism of action and neuroprotective efficacy of novel mitochondria-targeted compounds acting via different pathways to regulate CL/cyt c peroxidase activity. 5) Link bench to bedside confirming these important mechanisms and providing a means for monitoring the clinical effect of antioxidants and other therapies that may influence CL/cyt c peroxidase activity after severe TBI in infants and children. These studies will employ the newly developing technology of oxidative lipidomics to provide important mechanistic information on the role of cyt c -CL interactions in neuronal apoptosis after pediatric TBI. These specific aims will fill a major gap in knowledge since in vivo studies linking overall CL oxidation with cyt c release and apoptosis have been lacking. The release of cyt c from mitochondria is a critical early event in the mechanism of apoptosis. The ability to selectively modulate cyt c release could lead to targeted therapies for TBI and ultimately improve outcome for children. PROJECT NARRATIVE: Trauma in infants and children remains a significant cause of death and morbidity. Severe traumatic brain injury (TBI) is an important participant in this mortality and associated morbidity. This project will identify oxidized phospholipids functioning as signaling molecules in neuronal death after TBI using state of the art lipidomics approach. We will test novel compounds in experiments to prevent oxidative stress and neuronal death after TBI. The ability to selectively modulate this pathway could lead to targeted therapies for TBI and ultimately improve outcome for children.

描述（由申请人提供）：婴儿和儿童的创伤仍然是发病和死亡的一个重要原因。严重创伤性脑损伤（TBI）是导致死亡和相关发病率的重要因素。细胞凋亡导致 TBI 后神经元死亡。细胞色素 c (cyt c) 从线粒体内部线粒体空间的释放是线粒体介导的细胞凋亡的关键早期事件。当细胞色素 c 被挤出到细胞质中时，它会激活引发细胞凋亡和效应细胞的 caspase 级联，从而导致细胞凋亡。最近，我们展示了细胞色素 c 的新型氧化还原催化特性，这是通过其与线粒体中的 CL 和质膜中的 PS 相互作用导致其选择性氧化而实现的。所得产物 CL 和 PS 氢过氧化物在两条凋亡途径中充当重要信号，调节凋亡因子从线粒体释放到细胞质中，以及标记凋亡细胞进行吞噬作用的 PS 外化。我们的假设是，TBI 引发 ROS 的过量产生和磷脂的选择性早期氧化，氧化 CL 的积累触发线粒体释放促凋亡因子。因此，我们预测 TBI 诱导的 CL 氧化和细胞凋亡可以通过抗氧化策略和治疗来预防，通过饮食控制其脂肪酸残基来降低 CL 对氧化的敏感性。我们将利用从体外（神经元拉伸损伤）和体内模型（出生后 (PND) 17 只大鼠的受控皮质冲击 (CCI) 模型）到临床儿科 TBI 的综合方法来解决以下具体目标：1 ) 确定 CCI 后未成熟大脑中 ROS 产生、抗氧化剂消耗和 CL 氧化的程度、空间和时间模式 2) 研究性别是否影响 CCI 后未成熟大脑中 ROS 产生、抗氧化剂消耗和 CL 氧化TBI 以及拉伸损伤和谷氨酸暴露后的神经元。 3) 确定抗氧化剂和饮食控制抑制线粒体 CL 氧化并防止 TBI 后未成熟大脑以及拉伸损伤和谷氨酸暴露后神经元细胞凋亡的潜力 4) 设计和研究新型线粒体的作用机制和神经保护功效 -靶向化合物通过不同途径发挥作用，调节 CL/cyt c 过氧化物酶活性。 5) 将工作台与床边连接起来，确认这些重要机制，并提供一种监测抗氧化剂和其他可能影响婴儿和儿童严重 TBI 后 CL/cyt c 过氧化物酶活性的疗法的临床效果的方法。这些研究将采用新开发的氧化脂质组学技术，为儿科 TBI 后细胞色素 c -CL 相互作用在神经元凋亡中的作用提供重要的机制信息。这些具体目标将填补知识上的重大空白，因为一直缺乏将整体 CL 氧化与细胞色素 c 释放和细胞凋亡联系起来的体内研究。线粒体释放细胞色素 c 是细胞凋亡机制中关键的早期事件。选择性调节细胞色素 c 释放的能力可能会导致 TBI 的靶向治疗，并最终改善儿童的预后。项目叙述：婴儿和儿童的创伤仍然是死亡和发病的重要原因。严重创伤性脑损伤（TBI）是导致死亡和相关发病率的重要因素。该项目将使用最先进的脂质组学方法来鉴定在 TBI 后神经元死亡中充当信号分子的氧化磷脂。我们将在实验中测试新化合物，以预防 TBI 后的氧化应激和神经元死亡。选择性调节这一通路的能力可能会导致 TBI 的靶向治疗，并最终改善儿童的预后。